U.S. patent application number 14/573615 was filed with the patent office on 2015-04-16 for substituted hydroxamic acids and uses thereof.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. The applicant listed for this patent is Christopher Blackburn, Kenneth M. Gigstad, He Xu. Invention is credited to Christopher Blackburn, Kenneth M. Gigstad, He Xu.
Application Number | 20150105418 14/573615 |
Document ID | / |
Family ID | 45698052 |
Filed Date | 2015-04-16 |
United States Patent
Application |
20150105418 |
Kind Code |
A1 |
Blackburn; Christopher ; et
al. |
April 16, 2015 |
SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
Abstract
This invention provides compounds of formula (I): ##STR00001##
wherein R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2a, R.sup.2b,
X.sub.1, X.sub.2, and G have values as described in the
specification, useful as inhibitors of HDAC6. The invention also
provides pharmaceutical compositions comprising the compounds of
the invention and methods of using the compositions in the
treatment of proliferative, inflammatory, infectious, neurological
or cardiovascular diseases or disorders.
Inventors: |
Blackburn; Christopher;
(Natick, MA) ; Gigstad; Kenneth M.; (Westford,
MA) ; Xu; He; (Needham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Blackburn; Christopher
Gigstad; Kenneth M.
Xu; He |
Natick
Westford
Needham |
MA
MA
MA |
US
US
US |
|
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
|
Family ID: |
45698052 |
Appl. No.: |
14/573615 |
Filed: |
December 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13905171 |
May 30, 2013 |
8952163 |
|
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14573615 |
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13217401 |
Aug 25, 2011 |
8471026 |
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13905171 |
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61426319 |
Dec 22, 2010 |
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61425886 |
Dec 22, 2010 |
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61377238 |
Aug 26, 2010 |
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Current U.S.
Class: |
514/300 ;
546/122 |
Current CPC
Class: |
C07D 215/54 20130101;
A61P 35/00 20180101; A61K 31/4375 20130101; A61P 35/02 20180101;
C07D 471/04 20130101 |
Class at
Publication: |
514/300 ;
546/122 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1. A compound of formula (I): ##STR00080## or a pharmaceutically
acceptable salt thereof; wherein: one of X.sub.1 and X.sub.2 is
CR.sup.1 and the other is N; or both X.sub.1 and X.sub.2 are N; one
of R.sup.2a and R.sup.2b is R.sup.1, and the other is
--C(O)--NH--OH; R.sup.1a is hydrogen, fluoro, C.sub.1-4 alkyl, or
C.sub.1-4 fluoroalkyl; R.sup.1b is hydrogen, fluoro, C.sub.1-4
alkyl, or C.sub.1-4 fluoroalkyl; or R.sup.1a and R.sup.1b are taken
together to form a 3 to 6 membered cycloaliphatic; R.sup.1c and
R.sup.1d are: I) each occurrence of R.sup.1c is independently
hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl; and
each occurrence of R.sup.1d is independently hydrogen, fluoro,
C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl; or II) two occurrences
of R.sup.1c are taken together to form .dbd.O; and each occurrence
of R.sup.1d is independently hydrogen, fluoro, C.sub.1-4 alkyl, or
C.sub.1-4 fluoroalkyl; or III) two occurrences of R.sup.1d are
taken together to form .dbd.O; and each occurrence of R.sup.1c is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, --O--C.sub.1-4 alkyl, cyano, hydroxy, C.sub.1-4
alkyl, or C.sub.1-4 fluoroalkyl; G is --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3,
-L.sub.2-V.sub.1--R.sup.3, L.sub.2-V.sub.2--R.sup.3,
--V.sub.1-L.sub.1-V.sub.2--R.sup.3, or -L.sub.1-R.sup.3; L.sub.1 is
unsubstituted or substituted C.sub.1-3 alkylene chain; L.sub.2 is
unsubstituted or substituted C.sub.2-3 alkylene chain; V.sub.1 is
--C(O)--, --C(S)--, --C(O)--N(R.sup.4a)--, --C(O)--O--,
--S(O).sub.2--, or --SO.sub.2--N(R.sup.4a)--; V.sub.2 is
--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--, --N(R.sup.4a)--SO.sub.2--,
--SO.sub.2--N(R.sup.4a)--, --SO.sub.2--, --C(O)--, --C(O)--O--,
--O--C(O)--, --O--, --S--, --N(R.sup.4a)--C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--O--, --O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--; R.sup.3 is unsubstituted or
substituted C.sub.1-6 aliphatic, unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; and each occurrence of
R.sup.4a is independently hydrogen, or unsubstituted or substituted
C.sub.1-4 aliphatic.
2. The compound of claim 1, wherein: R.sup.2a is C(O)--NH--OH;
R.sup.2b is R.sup.1; and X.sub.1 is CR.sup.1 and X.sub.2 is N.
3. The compound of claim 1, wherein: G is --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
and V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
4. The compound of claim 1, wherein: each occurrence of R.sup.1 is
independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy,
ethoxy, trifluoromethyl, methyl, or ethyl.
5. The compound of claim 1, wherein: R.sup.1a is hydrogen, fluoro,
or methyl; R.sup.1b is hydrogen, fluoro, or methyl; each occurrence
of R.sup.1c is independently hydrogen, fluoro, or methyl; and each
occurrence of R.sup.1d is independently hydrogen, fluoro, or
methyl.
6. The compound of claim 1, wherein: each substitutable carbon
chain atom in R.sup.3 is unsubstituted or substituted with 1-2
occurrences of --R.sup.5dd; each substitutable saturated ring
carbon atom in R.sup.3 is unsubstituted or substituted with .dbd.O,
.dbd.C(R.sup.5).sub.2, or --R.sup.5aa; each substitutable
unsaturated ring carbon atom in R.sup.3 is unsubstituted or is
substituted with --R.sup.5a; each substitutable ring nitrogen atom
in R.sup.3 is unsubstituted or substituted with --R.sup.9b; each
R.sup.5a is independently halogen, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --C.ident.C--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2, --C(O)R.sup.6,
--C(O)N(R.sup.4).sub.2, --N(R.sup.4)SO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2N(R.sup.4).sub.2, unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; or two adjacent R.sup.5a, taken
together with the intervening ring atoms, form an unsubstituted or
substituted fused 5-10 membered aromatic ring or an unsubstituted
or substituted 4-10 membered non-aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; each occurrence of R.sup.5aa is independently chloro,
fluoro, hydroxy, unsubstituted or substituted C.sub.1-6 aliphatic,
--O(C.sub.1-6 alkyl), --C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
fluoroalkyl, cyano, --N(R.sup.4).sub.2, --C(O)(C.sub.1-6 alkyl),
--CO.sub.2H, --C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl),
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)C.sub.1-6 alkyl,
--NHC(O)OC.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl, or
--NHS(O).sub.2C.sub.1-6 alkyl; each occurrence of R.sup.5dd is
independently fluoro, hydroxy, --O(C.sub.1-6 alkyl), cyano,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-6 alkyl), --CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl).sub.2, --NHC(O)C.sub.1-6 alkyl, --NHC(O)OC.sub.1-6 alkyl,
--NHC(O)NHC.sub.1-6 alkyl, or --NHS(O).sub.2C.sub.1-6 alkyl; each
R.sup.4 is independently hydrogen, unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; or two R.sup.4 on the same nitrogen
atom, taken together with the nitrogen atom, form an unsubstituted
or substituted 5- to 6-membered heteroaryl or an unsubstituted or
substituted 4- to 8-membered heterocyclyl having, in addition to
the nitrogen atom, 0-2 ring heteroatoms selected from nitrogen,
oxygen, and sulfur; each R.sup.5 is independently hydrogen,
unsubstituted or substituted C.sub.1-6 aliphatic, unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur. each
R.sup.6 is independently unsubstituted or substituted C.sub.1-6
aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; each R.sup.9b is independently
--C(O)R.sup.6, --C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, unsubstituted
C.sub.3-10 cycloaliphatic, C.sub.3-10 cycloaliphatic substituted
with 1-2 independent occurrences of R.sup.7 or R.sup.8,
unsubstituted C.sub.1-6 aliphatic, or C.sub.1-6 aliphatic
substituted with 1-2 independent occurrences of R.sup.7 or R.sup.8;
each R.sup.7 is independently unsubstituted or substituted
4-10-membered heterocyclyl having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; and each R.sup.8 is
independently chloro, fluoro, --OH, --O(C.sub.1-6 alkyl), --CN,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-6 alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-6
alkyl), or --C(O)N(C.sub.1-6 alkyl).sub.2.
7. The compound of claim 6, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5aa; the total number of R.sup.5a and R.sup.5aa
substituents is p; p is 1-4; each R.sup.5a is independently
halogen, cyano, nitro, hydroxy, unsubstituted C.sub.1-6 aliphatic,
C.sub.1-6 aliphatic substituted with 1-2 independent occurrences of
R.sup.7 or R.sup.8, unsubstituted O--C.sub.1-6 alkyl,
--O--C.sub.1-6 alkyl substituted with 1-2 independent occurrences
of R.sup.7 or R.sup.8, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
fluoroalkyl, --NHC(O)R.sup.6, --C(O)NH(R.sup.4),
--NHC(O)O--C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl,
--NHS(O).sub.2C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, 3-10-membered cycloaliphatic substituted with 0-2
occurrences of --R.sup.7a, 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur substituted with 0-2 occurrences of R.sup.7a, 6-10-membered
aryl substituted with 0-2 occurrences of --R.sup.7a, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur substituted with 0-2
occurrences of --R.sup.7a, and each occurrence of R.sup.7a is
independently chloro, fluoro, C.sub.1-6 aliphatic, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --CO.sub.2H, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6
alkyl, --N(C.sub.1-6 alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6 alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
8. The compound of claim 6, represented by formula (II-a-i):
##STR00081##
9. The compound of claim 8, wherein: G is --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
and V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
10. The compound of claim 9, wherein: each occurrence of R.sup.1 is
independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy,
ethoxy, trifluoromethyl, methyl, or ethyl.
11. The compound of claim 9, wherein: R.sup.1a is hydrogen, fluoro,
or methyl; R.sup.1b is hydrogen, fluoro, or methyl; each occurrence
of R.sup.1c is independently hydrogen, fluoro, or methyl; and each
occurrence of R.sup.1d is independently hydrogen, fluoro, or
methyl.
12. The compound of claim 9, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5aa; the total number of R.sup.5a and R.sup.5aa
substituents is p; p is 1-4; each R.sup.5a is independently
halogen, cyano, nitro, hydroxy, unsubstituted C.sub.1-6 aliphatic,
C.sub.1-6 aliphatic substituted with 1-2 independent occurrences of
R.sup.7 or R.sup.8, unsubstituted --O--C.sub.1-6 alkyl,
--O--C.sub.1-6 alkyl substituted with 1-2 independent occurrences
of R.sup.7 or R.sup.8, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
fluoroalkyl, --NHC(O)R.sup.6, --C(O)NH(R.sup.4),
--NHC(O)O--C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl,
--NHS(O).sub.2C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, 3-10-membered cycloaliphatic substituted
with 0-2 occurrences of R.sup.7a, 4-10-membered heterocyclyl having
1-4 heteroatoms independently selected from nitrogen, oxygen, and
sulfur substituted with 0-2 occurrences of R.sup.7a, 6-10-membered
aryl substituted with 0-2 occurrences of R.sup.7a, or 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of
--R.sup.7a, and each occurrence of R.sup.7a is independently
chloro, fluoro, C.sub.1-6 aliphatic, C.sub.1-6 fluoroalkyl,
--O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl, cyano, hydroxy,
--CO.sub.2H, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
13. The compound of claim 12, wherein: R.sup.1a is hydrogen;
R.sup.1b is hydrogen; each occurrence of R.sup.1c is hydrogen; each
occurrence of R.sup.1d is hydrogen; and each occurrence of R.sup.1
is hydrogen.
14. The compound of claim 6, represented by formula (II-a-ii):
##STR00082##
15. The compound of claim 14, wherein: G is --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
and V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
16. The compound of claim 15, wherein: each occurrence of R.sup.1
is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy,
ethoxy, trifluoromethyl, methyl, or ethyl.
17. The compound of claim 15, wherein: R.sup.1a is hydrogen,
fluoro, or methyl; R.sup.1b is hydrogen, fluoro, or methyl; each
occurrence of R.sup.1c is independently hydrogen, fluoro, or
methyl; and each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl.
18. The compound of claim 15, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5aa; the total number of R.sup.5a and R.sup.5aa
substituents is p; p is 1-4; each R.sup.5a is independently
halogen, cyano, nitro, hydroxy, unsubstituted C.sub.1-6 aliphatic,
C.sub.1-6 aliphatic substituted with 1-2 independent occurrences of
R.sup.7 or R.sup.8, unsubstituted O--C.sub.1-6 alkyl,
--O--C.sub.1-6 alkyl substituted with 1-2 independent occurrences
of R.sup.7 or R.sup.8, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
fluoroalkyl, --NHC(O)R.sup.6, --C(O)NH(R.sup.4),
--NHC(O)O--C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl,
--NHS(O).sub.2C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, 3-10-membered cycloaliphatic substituted
with 0-2 occurrences of R.sup.7a, 4-10-membered heterocyclyl having
1-4 heteroatoms independently selected from nitrogen, oxygen, and
sulfur substituted with 0-2 occurrences of R.sup.7a, 6-10-membered
aryl substituted with 0-2 occurrences of --R.sup.7a, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur substituted with 0-2
occurrences of --R.sup.7a, and each occurrence of R.sup.7a is
independently chloro, fluoro, C.sub.1-6 aliphatic, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --CO.sub.2H, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6
alkyl, --N(C.sub.1-6alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6alkyl).sub.2, --NHC(O)NHC.sub.1-6alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
19. The compound of claim 18, wherein: R.sup.1a is hydrogen;
R.sup.1b is hydrogen; each occurrence of R.sup.1c is hydrogen; each
occurrence of R.sup.1d is hydrogen; and each occurrence of R.sup.1
is hydrogen.
20. The compound of claim 6, represented by formula (II-b-i):
##STR00083##
21. The compound of claim 20, wherein: G is --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
and V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
22. The compound of claim 21, wherein: each occurrence of R.sup.1
is independently hydrogen, chloro, fluoro, cyano, hydroxy, methoxy,
ethoxy, trifluoromethyl, methyl, or ethyl.
23. The compound of claim 21, wherein: R.sup.1a is hydrogen,
fluoro, or methyl; R.sup.1b is hydrogen, fluoro, or methyl; each
occurrence of R.sup.1c is independently hydrogen, fluoro, or
methyl; and each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl.
24. The compound of claim 21, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5aa; the total number of R.sup.5a and R.sup.5aa
substituents is p; p is 1-4; each R.sup.5a is independently
halogen, cyano, nitro, hydroxy, unsubstituted C.sub.1-6 aliphatic,
C.sub.1-6 aliphatic substituted with 1-2 independent occurrences of
R.sup.7 or R.sup.8, unsubstituted --O--C.sub.1-6 alkyl,
--O--C.sub.1-6 alkyl substituted with 1-2 independent occurrences
of R.sup.7 or R.sup.8, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
fluoroalkyl, --NHC(O)R.sup.6, --C(O)NH(R.sup.4),
--NHC(O)O--C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl,
--NHS(O).sub.2C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, 3-10-membered cycloaliphatic substituted
with 0-2 occurrences of R.sup.7a, 4-10-membered heterocyclyl having
1-4 heteroatoms independently selected from nitrogen, oxygen, and
sulfur substituted with 0-2 occurrences of --R.sup.7a,
6-10-membered aryl substituted with 0-2 occurrences of --R.sup.7a,
or 5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur substituted with 0-2
occurrences of --R.sup.7a, and each occurrence of R.sup.7a is
independently chloro, fluoro, C.sub.1-6 aliphatic, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --CO.sub.2H, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6
alkyl, --N(C.sub.1-6 alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
25. The compound of claim 24, wherein: R.sup.1a is hydrogen;
R.sup.1b is hydrogen; each occurrence of R.sup.1c is hydrogen; each
occurrence of R.sup.1d is hydrogen; and each occurrence of R.sup.1
is hydrogen.
26. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
27. A method of treating a proliferative disorder in a patient
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
28. The method of claim 27, wherein the proliferative disorder is
breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute
myelogenous leukemia, or acute lymphoblastic leukemia.
29. A method for inhibiting HDAC6 activity in a patient comprising
administering a pharmaceutical composition comprising an amount of
a compound of claim 1 effective to inhibit HDAC6 activity in the
patient.
Description
PRIORITY CLAIM
[0001] The present application is a continuation of U.S. patent
application Ser. No. 13/905,171, filed May 30, 2013, which is a
continuation of U.S. patent application Ser. No. 13/217,401, filed
Aug. 25, 2011, which claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application Ser. No.
61/377,238 filed Aug. 26, 2010, incorporated by reference in its
entirety, and U.S. Provisional Patent Application Ser. No.
61/426,319, filed Dec. 22, 2010, incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to compounds and methods for the
selective inhibition of HDAC6. The present invention relates to
compounds useful as HDAC6 inhibitors. The invention also provides
pharmaceutical compositions comprising the compounds of the
invention and methods of using the compositions in the treatment of
various diseases.
BACKGROUND OF THE INVENTION
[0003] Histone deacetylase 6 (HDAC6) is a member of a family of
amidohydrolases commonly referred as histone or lysine deacetylases
(HDACs or KDACs) as they catalyze the removal of acetyl groups from
the 6-amino group of lysine residues from proteins. The family
includes 18 enzymes which can be divided in 3 main classes based on
their sequence homology to yeast enzymes Rpd3 (Class I), Hda1
(Class II) and Sir2 (Class III). A fourth class was defined with
the finding of a distinct mammalian enzyme--HDAC11 (reviewed in
Yang, et al., Nature Rev. Mol. Cell Biol. 2008, 9:206-218 and in
Saunders and Verdin, Oncogene 2007, 26(37):5489-5504).
Biochemically, Class I (HDAC1, 2, 3, 8) and Class II (HDAC4, 5, 6,
7, 9, 10) and Class IV (HDAC11) are Zn.sup.2+-dependent enzymes,
while Class III (SIRT1-7) are dependent on nicotinamide adenine
dinucleotide (NAD.sup.+) for activity. Unlike all other HDACs,
HDAC6 resides primarily in the cytosol. It has 2 functional
catalytic domains and a carboxy-terminal Zn.sup.2+-finger ubiquitin
binding domain that binds ubiquitinated misfolded proteins
(Kawaguchi et al., Cell 2003, 115(6):727-738), ubiquitin (Boyaullt
et al., EMBO J. 2006, 25(14): 3357-3366), as well as ubiquitin-like
FAT10 modifier (Kalveram et al., J. Cell Sci. 2008,
121(24):4079-4088). Known substrates of HDAC6 include cytoskeletal
proteins .alpha.-tubulin and cortactin; .beta.-catenin which forms
part of adherens junctions and anchors the actin cytoskeleton; the
chaperone Hsp90; and the redox regulatory proteins peroxiredoxin
(Prx) I and Prx II (reviewed in Boyault et al., Oncogene 2007,
26(37):5468-5476; Matthias et al., Cell Cycle 2008, 7(1):7-10; Li
et al., J Biol. Chem. 2008, 283(19):12686-12690; Parmigiani et al.,
Proc. Natl. Acad. Sci. USA 2009, 105(28):9633-9638). Thus, HDAC6
mediates a wide range of cellular functions including
microtubule-dependent trafficking and signaling, membrane
remodeling and chemotactic motility, involvement in control of
cellular adhesion, ubiquitin level sensing, regulation of chaperone
levels and activity, and responses to oxidative stress. All of
these functions may be important in tumorigenesis, tumor growth and
survival as well as metastasis (Simms-Waldrip et al., Mol. Genet.
Metabolism 2008, 94(3):283-286; Rodriguez-Gonzalez et al., Cancer
Res. 2008, 68(8):2557-2560; Kapoor, Int. J. Cancer 2009, 124:509;
Lee et al., Cancer Res. 2008, 68(18):7561-7569). Recent studies
have shown HDAC6 to be important in autophagy, an alternative
pathway for protein degradation that compensates for deficiencies
in the activity of the ubiquitin proteasome system or expression of
proteins prone to form aggregates and can be activated following
treatment with a proteasome inhibitor (Kawaguchi et al., Cell 2003,
115(6):727-738; Iwata et al., J. Biol. Chem. 2005, 280(48):
40282-40292; Ding et al., Am. J. Pathol. 2007, 171:513-524, Pandey
et al., Nature 2007, 447(7146):860-864). Although the molecular
mechanistic details are not completely understood, HDAC6 binds
ubiquitinated or ubiquitin-like conjugated misfolded proteins which
would otherwise induce proteotoxic stress and then serves as an
adaptor protein to traffic the ubiquitinated cargo to the
microtubule organizing center using the microtubule network via its
known association with dynein motor protein. The resulting
perinuclear aggregates, known as aggresomes, are then degraded by
fusion with lysosomes in an HDAC6- and cortactin-dependent process
which induces remodeling of the actin cytoskeleton proximal to
aggresomes (Lee et al., EMBO J. 2010, 29:969-980). In addition,
HDAC6 regulates a variety of biological processes dependent on its
association with the microtubular network including cellular
adhesion (Tran et al., J. Cell Sci. 2007, 120(8):1469-1479) and
migration (Zhang et al., Mol. Cell 2007, 27(2):197-213; reviewed in
Valenzuela-Femandez et al., Trends Cell. Biol. 2008,
18(6):291-297), epithelial to mesenchymal transition (Shan et al.,
J. Biol. Chem. 2008, 283(30):21065-21073), resistance to anoikis
(Lee et al., Cancer Res. 2008, 68(18):7561-7569), epithelial growth
factor-mediated Wnt signaling via .beta.-catenin deacetylation (Li
et al., J. Biol. Chem. 2008, 283(19):12686-12690) and epithelial
growth factor receptor stabilization by endocytic trafficking
(Lissanu Deribe et al., Sci. Signal. 2009, 2(102): ra84; Gao et
al., J. Biol. Chem. 2010, 285:11219-11226); all events that promote
oncogenesis and metastasis (Lee et al., Cancer Res. 2008,
68(18):7561-7569). HDAC6 activity is known to be upregulated by
Aurora A kinase in cilia formation (Pugacheva et al., Cell 2007,
129(7):1351-1363) and indirectly by farnesyl transferase with which
HDAC6 forms a complex with microtubules (Zhou et al., J. Biol.
Chem. 2009, 284(15): 9648-9655). Also, HDAC6 is negatively
regulated by tau protein (Perez et al., J. Neurochem. 2009,
109(6):1756-1766).
[0004] Diseases in which selective HDAC6 inhibition could have a
potential benefit include cancer (reviewed in Simms-Waldrip et al.,
Mol. Genet. Metabolism 2008, 94(3):283-286 and Rodriguez-Gonzalez
et al., Cancer Res. 2008, 68(8):2557-2560), specifically: multiple
myeloma (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005,
102(24):8567-8572); lung cancer (Kamemura et al., Biochem. Biophys.
Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro et al.,
Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et
al., Cancer Res. 2008, 68(18):7561-7569); prostate cancer (Mellado
et al., Clin. Trans. Onco. 2009, 11(1):5-10); pancreatic cancer
(Nawrocki et al., Cancer Res. 2006, 66(7):3773-3781); renal cancer
(Cha et al., Clin. Cancer Res. 2009, 15(3):840-850); and leukemias
such as acute myeloid leukemia (AML) (Fiskus et al., Blood 2008,
112(7):2896-2905) and acute lymphoblastic leukemia (ALL)
(Rodriguez-Gonzalez et al., Blood 2008, 112(11): Abstract
1923).
[0005] Inhibition of HDAC6 may also have a role in cardiovascular
disease, i.e. cardiovascular stress, including pressure overload,
chronic ischemia, and infarction-reperfusion injury (Tannous et
al., Circulation 2008, 117(24):3070-3078); bacterial infection,
including those caused by uropathogenic Escherichia coli (Dhakal
and Mulve, J. Biol. Chem. 2008, 284(1):446-454); neurological
diseases caused by accumulation of intracellular protein aggregates
such as Huntington's disease (reviewed in Kazantsev et al., Nat.
Rev. Drug Disc. 2008, 7(10):854-868; see also Dompierre et al., J.
Neurosci. 2007, 27(13):3571-3583; Kozikowski et al., J. Med. Chem.
2007, 50:3054-3061) or central nervous system trauma caused by
tissue injury, oxidative-stress induced neuronal or axomal
degeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009,
106(46):19599-195604); and inflammation, including reduction of
pro-inflammatory cytokine IL-113 (Carta et al., Blood 2006,
108(5):1618-1626), increased expression of the FOXP3 transcription
factor, which induces immunosuppressive function of regulatory
T-cells resulting in benefits in chronic diseases such as
rheumatoid arthritis, psoriasis, multiple sclerosis, lupus and
organ transplant rejection (reviewed in Wang et al., Nat. Rev. Drug
Disc. 2009, 8(12):969-981).
[0006] Given the complex function of HDAC6, selective inhibitors
could have potential utility when used alone or in combination with
other chemotherapeutics such as microtubule destabilizing agents
(Zhou et al., J. Biol. Chem. 2009, 284(15): 9648-9655); Hsp90
inhibitors (Rao et al., Blood 2008, 112(5)1886-1893); inhibitors of
Hsp90 client proteins, including receptor tyrosine kinases such as
Her-2 or VEGFR (Bhalla et al., J. Clin. Oncol. 2006, 24(18S):
Abstract 1923; Park et al., Biochem. Biophys. Res. Commun. 2008,
368(2):318-322), and signaling kinases such as Bcr-Abl, Akt, mutant
FLT-3, c-Raf, and MEK (Bhalla et al., J. Clin. Oncol. 2006,
24(18S): Abstract 1923; Kamemura et al., Biochem. Biophys. Res.
Commun. 2008, 374(1):84-89); inhibitors of cell cycle kinases
Aurora A and Aurora B (Pugacheva et al., Cell 2007,
129(7):1351-1363; Park et al., J. Mol. Med 2008, 86(1):117-128; Cha
et al., Clin. Cancer Res. 2009, 15(3):840-850); EGFR inhibitors
(Lissanu Deribe et al., Sci. Signal. 2009, 2(102): ra84; Gao et
al., J. Biol. Chem. 2010, 285:11219-11226) and proteasome
inhibitors (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005,
102(24):8567-8572) or other inhibitors of the ubiquitin proteasome
system such as ubiquitin and ubiqutin-like activating (E1),
conjugation (E2), ligase enzymes (E3, E4) and deubiquitinase
enzymes (DUBs) as well as modulators of autophagy and protein
homeostasis pathways. In addition, HDAC6 inhibitors could be
combined with radiation therapy (Kim et al., Radiother. Oncol.
2009, 92(1):125-132.
[0007] Clearly, it would be beneficial to provide novel HDAC6
inhibitors that possess good therapeutic properties, especially for
the treatment of proliferative diseases or disorders.
DETAILED DESCRIPTION OF THE INVENTION
I. General Description of Compounds of the Invention
[0008] The present invention provides compounds that are effective
inhibitors of HDAC6. These compounds are useful for inhibiting
HDAC6 activity in vitro and in vivo, and are especially useful for
the treatment of various cell proliferative diseases or disorders.
The compounds of the invention are represented by formula (I):
##STR00002##
[0009] or a pharmaceutically acceptable salt thereof;
[0010] wherein:
[0011] one of X.sub.1 and X.sub.2 is CR.sup.1 and the other is N;
or both X.sub.1 and X.sub.2 are N; [0012] one of R.sup.2a and
R.sup.2b is R.sup.1, and the other is --C(O)--NH--OH;
[0013] R.sup.1a is hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; [0014] R.sup.1b is hydrogen, fluoro, C.sub.1-4 alkyl,
or C.sub.1-4 fluoroalkyl;
[0015] or R.sup.1a and R.sup.1b are taken together to form a 3 to 6
membered cycloaliphatic;
[0016] R.sup.1c and R.sup.1d are: [0017] I) each occurrence of
R.sup.1c is independently hydrogen, fluoro, C.sub.1-4 alkyl, or
C.sub.1-4 fluoroalkyl; and each occurrence of R.sup.1d is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; or [0018] II) two occurrences of R.sup.1c are taken
together to form .dbd.O; and each occurrence of R.sup.1d is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; or [0019] III) two occurrences of R.sup.1d are taken
together to form .dbd.O; and each occurrence of R.sup.1c is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl;
[0020] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, --O--C.sub.1-4 alkyl, cyano, hydroxy, C.sub.1-4
alkyl, or C.sub.1-4 fluoroalkyl;
[0021] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1R.sup.3, -L.sub.2-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, --V.sub.1-L.sub.1-V.sub.2--R.sup.3, or
-L.sub.1-R.sup.3;
[0022] L.sub.1 is unsubstituted or substituted C.sub.1-3 alkylene
chain;
[0023] L.sub.2 is unsubstituted or substituted C.sub.2-3 alkylene
chain;
[0024] V.sub.1 is --C(O)--, --C(S)--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, --S(O).sub.2--, or --SO.sub.2--N(R.sup.4a)--;
[0025] V.sub.2 is --N(R.sup.4a)--, N(R.sup.4a)--C(O)--,
--N(R.sup.4a)--SO.sub.2--, --SO.sub.2--N(R.sup.4a)--, --SO.sub.2--,
--C(O)--, --C(O)--O--, --O--C(O)--, --O--, --S--,
--N(R.sup.4a)--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--O--,
--O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--;
[0026] R.sup.3 is unsubstituted or substituted C.sub.1-6 aliphatic,
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; and
[0027] each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic.
2. Compounds and Definitions
[0028] Compounds of this invention include those described
generally for formula (I) above, and are further illustrated by the
classes, subclasses, and species disclosed herein. As used herein,
the following definitions shall apply unless otherwise
indicated.
[0029] As described herein, compounds of the invention may be
optionally substituted with one or more substituents, such as are
illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, means that a hydrogen radical of the
designated moiety is replaced with the radical of a specified
substituent, provided that the substitution results in a stable or
chemically feasible compound. The term "substitutable", when used
in reference to a designated atom, means that attached to the atom
is a hydrogen radical, which hydrogen atom can be replaced with the
radical of a suitable substituent. Unless otherwise indicated, an
"optionally substituted" group may have a substituent at each
substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at every position. Combinations
of substituents envisioned by this invention are preferably those
that result in the formation of stable or chemically feasible
compounds.
[0030] A stable compound or chemically feasible compound is one in
which the chemical structure is not substantially altered when kept
at a temperature from about -80.degree. C. to about +40.degree. C.,
in the absence of moisture or other chemically reactive conditions,
for at least a week, or a compound which maintains its integrity
long enough to be useful for therapeutic or prophylactic
administration to a patient.
[0031] The phrase "one or more substituents", as used herein,
refers to a number of substituents that equals from one to the
maximum number of substituents possible based on the number of
available bonding sites, provided that the above conditions of
stability and chemical feasibility are met.
[0032] As used herein, the term "independently selected" means that
the same or different values may be selected for multiple instances
of a given variable in a single compound.
[0033] As used herein, the term "aromatic" includes aryl and
heteroaryl groups as described generally below and herein.
[0034] The term "aliphatic" or "aliphatic group", as used herein,
means an optionally substituted straight-chain or branched
C.sub.1-12 hydrocarbon. For example, suitable aliphatic groups
include optionally substituted linear, or branched alkyl, alkenyl,
alkynyl groups and hybrids thereof. Unless otherwise specified, in
various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6,
1-4, 1-3, or 1-2 carbon atoms.
[0035] The term "alkyl", used alone or as part of a larger moiety,
refers to an optionally substituted straight or branched chain
hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2
carbon atoms.
[0036] The term "alkenyl", used alone or as part of a larger
moiety, refers to an optionally substituted straight or branched
chain hydrocarbon group having at least one double bond and having
2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
[0037] The term "alkynyl", used alone or as part of a larger
moiety, refers to an optionally substituted straight or branched
chain hydrocarbon group having at least one triple bond and having
2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
[0038] The terms "cycloaliphatic", "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic", used alone or as part of a larger
moiety, refer to an optionally substituted saturated or partially
unsaturated cyclic aliphatic ring system having from 3 to about 14
ring carbon atoms. In some embodiments, the cycloaliphatic group is
an optionally substituted monocyclic hydrocarbon having 3-10, 3-8
or 3-6 ring carbon atoms. Cycloaliphatic groups include, without
limitation, optionally substituted cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl. The
terms "cycloaliphatic", "carbocycle", "carbocyclyl", "carbocyclo",
or "carbocyclic" also include optionally substituted bridged or
fused bicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms,
wherein any individual ring in the bicyclic system has 3-8 ring
carbon atoms.
[0039] The term "cycloalkyl" refers to an optionally substituted
saturated ring system of about 3 to about 10 ring carbon atoms.
Exemplary monocyclic cycloalkyl rings include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0040] The term "cycloalkenyl" refers to an optionally substituted
non-aromatic monocyclic or multicyclic ring system containing at
least one carbon-carbon double bond and having about 3 to about 10
carbon atoms. Exemplary monocyclic cycloalkenyl rings include
cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[0041] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, which is substituted with one or more halogen
atoms. As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic
wherein the halogen is fluoro, including perfluorinated aliphatic
groups. Examples of fluoroaliphatic groups include, without
limitation, fluoromethyl, difluoromethyl, trifluoromethyl,
2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl,
1,2,2-trifluoroethyl, and pentafluoroethyl.
[0042] The term "heteroatom" refers to one or more of oxygen,
sulfur, nitrogen, phosphorus, or silicon (including, any oxidized
form of nitrogen, sulfur, phosphorus, or silicon; the quaternized
form of any basic nitrogen or; a substitutable nitrogen of a
heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl),
NH (as in pyrrolidinyl) or NR+ (as in N-substituted
pyrrolidinyl)).
[0043] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to an optionally substituted C.sub.6-14aromatic hydrocarbon
moiety comprising one to three aromatic rings. Preferably, the aryl
group is a C.sub.6-10aryl group. Aryl groups include, without
limitation, optionally substituted phenyl, naphthyl, or
anthracenyl. The terms "aryl" and "ar-", as used herein, also
include groups in which an aryl ring is fused to one or more
cycloaliphatic rings to form an optionally substituted cyclic
structure such as a tetrahydronaphthyl, indenyl, or indanyl ring.
The term "aryl" may be used interchangeably with the terms "aryl
group", "aryl ring", and "aromatic ring".
[0044] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10arylC.sub.1-6alkyl, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0045] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., "heteroaralkyl", or
"heteroaralkoxy", refer to groups having 5 to 14 ring atoms,
preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 .pi.
electrons shared in a cyclic array; and having, in addition to
carbon atoms, from one to five heteroatoms. In some embodiments,
the heteroaryl group has 5-10 ring atoms, having, in addition to
carbon atoms, from one to five heteroatoms. A heteroaryl group may
be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroatom"
refers to nitrogen, oxygen, or sulfur, and includes any oxidized
form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen. For example, a nitrogen atom of a heteroaryl may be a
basic nitrogen atom and may also be optionally oxidized to the
corresponding N-oxide. When a heteroaryl is substituted by a
hydroxy group, it also includes its corresponding tautomer. The
terms "heteroaryl" and "heteroar-", as used herein, also include
groups in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples
of heteroaryl groups include thienyl, furanyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
The term "heteroaryl" may be used interchangeably with the terms
"heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of
which terms include rings that are optionally substituted. The term
"heteroaralkyl" refers to an alkyl group substituted by a
heteroaryl, wherein the alkyl and heteroaryl portions independently
are optionally substituted.
[0046] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 4-10 membered ring,
preferably a 3- to 8-membered monocyclic or 7-10-membered bicyclic
heterocyclic moiety that is either saturated or partially
unsaturated, and having, in addition to carbon atoms, one or more,
preferably one to four, heteroatoms, as defined above. When used in
reference to a ring atom of a heterocycle, the term "nitrogen"
includes a substituted nitrogen. As an example, in a saturated or
partially unsaturated ring having 0-3 heteroatoms selected from
oxygen, sulfur or nitrogen, the nitrogen may be N (as in
3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in
N-substituted pyrrolidinyl).
[0047] A heterocyclic ring can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted. Examples
of such saturated or partially unsaturated heterocyclic radicals
include, without limitation, tetrahydrofuranyl, tetrahydrothienyl,
piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,
dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,
morpholinyl, and thiomorpholinyl. A heterocyclyl group may be
mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term
"heterocyclylalkyl" refers to an alkyl group substituted by a
heterocyclyl, wherein the alkyl and heterocyclyl portions
independently are optionally substituted. Additionally, a
heterocyclic ring also includes groups in which the heterocyclic
ring is fused to one or more aryl rings.
[0048] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having multiple sites of unsaturation, but is not
intended to include aromatic (e.g., aryl or heteroaryl) moieties,
as herein defined.
[0049] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n'--, wherein n' is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
An optionally substituted alkylene chain is a polymethylene group
in which one or more methylene hydrogen atoms is optionally
replaced with a substituent. Suitable substituents include those
described below for a substituted aliphatic group and also include
those described in the specification herein. It will be appreciated
that two substituents of the alkylene group may be taken together
to form a ring system. In certain embodiments, two substituents can
be taken together to form a 3-7-membered ring. The substituents can
be on the same or different atoms.
[0050] An alkylene chain also can be optionally interrupted by a
functional group. An alkylene chain is "interrupted" by a
functional group when an internal methylene unit is interrupted by
the functional group. Examples of suitable "interrupting functional
groups" are described in the specification and claims herein.
[0051] For purposes of clarity, all bivalent groups described
herein, including, e.g., the alkylene chain linkers described
above, are intended to be read from left to right, with a
corresponding left-to-right reading of the formula or structure in
which the variable appears.
[0052] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) group may contain one or more substituents and thus
may be "optionally substituted". In addition to the substituents
defined above and herein, suitable substituents on the unsaturated
carbon atom of an aryl or heteroaryl group also include and are
generally selected from -halo, --NO.sub.2, --CN, --R.sup.+,
--C(R.sup.+).dbd.C(R.sup.+).sub.2, --C.ident.C--R.sup.+,
--OR.sup.+, --SR.sup.o, --S(O)R.sup.o, --SO.sub.2R.sup.o,
--SO.sub.3R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --N(R.sup.+).sub.2,
--NR.sup.+C(O)R.sup.+, --NR.sup.4C(S)R.sup.+,
--NR.sup.+C(O)N(R.sup.+).sub.2, --NR.sup.+C(S)N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--R.sup.o, --NR.sup.+CO.sub.2R.sup.+,
--NR.sup.+SO.sub.2R.sup.o, --NR.sup.+SO.sub.2N(R.sup.+).sup.2,
--O--C(O)R.sup.+, --O--CO.sub.2R.sup.+, --OC(O)N(R.sup.+).sub.2,
--C(O)R.sup.+, --C(S)R.sup.o, --CO.sub.2R.sup.+,
--C(O)--C(O)R.sup.+, --C(O)N(R.sup.+).sub.2,
--C(S)N(R.sup.+).sub.2, --C(O)N(R.sup.+)--OR.sup.+,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R.sup.+,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR.sup.+,
--N(R.sup.+)--N(R.sup.+).sub.2,
--C(.dbd.NR.sup.+)--N(R.sup.+)--OR.sup.+,
--C(R.sup.o).dbd.N--OR.sup.+, --P(O)(R.sup.+).sub.2,
--P(O)(OR.sup.+).sub.2, --O--P(O)--OR.sup.+, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2, wherein R.sup.+, independently,
is hydrogen or an optionally substituted aliphatic, aryl,
heteroaryl, cycloaliphatic, or heterocyclyl group, or two
independent occurrences of R.sup.+ are taken together with their
intervening atom(s) to form an optionally substituted 5-7-membered
aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Each
R.sup.o is an optionally substituted aliphatic, aryl, heteroaryl,
cycloaliphatic, or heterocyclyl group.
[0053] An aliphatic or heteroaliphatic group, or a non-aromatic
carbycyclic or heterocyclic ring may contain one or more
substituents and thus may be "optionally substituted". Unless
otherwise defined above and herein, suitable substituents on the
saturated carbon of an aliphatic or heteroaliphatic group, or of a
non-aromatic carbocyclic or heterocyclic ring are selected from
those listed above for the unsaturated carbon of an aryl or
heteroaryl group and additionally include the following: .dbd.O,
.dbd.S, .dbd.C(R*).sub.2, .dbd.N--N(R*).sub.2, .dbd.N--OR*,
.dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup.o.dbd.N--NHSO.sub.2R.sup.o or .dbd.N--R*
where R.sup.o is defined above, and each R* is independently
selected from hydrogen or an optionally substituted C.sub.1-6
aliphatic group.
[0054] In addition to the substituents defined above and herein,
optional substituents on the nitrogen of a non-aromatic
heterocyclic ring also include and are generally selected from
--R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --C(O)OR.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --S(O).sub.2R.sup.+,
--S(O).sub.2N(R.sup.+).sub.2, --C(S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --N(R.sup.+)S(O).sub.2R.sup.+;
wherein each R.sup.+ is defined above. A ring nitrogen atom of a
heteroaryl or non-aromatic heterocyclic ring also may be oxidized
to form the corresponding N-hydroxy or N-oxide compound. A
nonlimiting example of such a heteroaryl having an oxidized ring
nitrogen atom is N-oxidopyridyl.
[0055] As detailed above, in some embodiments, two independent
occurrences of R.sup.+ (or any other variable similarly defined in
the specification and claims herein), are taken together with their
intervening atom(s) to form a monocyclic or bicyclic ring selected
from 3-13-membered cycloaliphatic, 3-12-membered heterocyclyl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0056] Exemplary rings that are formed when two independent
occurrences of R.sup.+ (or any other variable similarly defined in
the specification and claims herein), are taken together with their
intervening atom(s) include, but are not limited to the following:
a) two independent occurrences of R.sup.+ (or any other variable
similarly defined in the specification or claims herein) that are
bound to the same atom and are taken together with that atom to
form a ring, for example, N(R.sup.+).sub.2, where both occurrences
of R.sup.+ are taken together with the nitrogen atom to form a
piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R.sup.+ (or any other variable similarly
defined in the specification or claims herein) that are bound to
different atoms and are taken together with both of those atoms to
form a ring, for example where a phenyl group is substituted with
two occurrences of
##STR00003##
these two occurrences of R.sup.+ are taken together with the oxygen
atoms to which they are bound to form a fused 6-membered oxygen
containing ring:
##STR00004##
It will be appreciated that a variety of other rings (e.g., Spiro
and bridged rings) can be formed when two independent occurrences
of R+ (or any other variable similarly defined in the specification
and claims herein) are taken together with their intervening
atom(s) and that the examples detailed above are not intended to be
limiting.
[0057] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a 13C- or 14C-enriched carbon are within the scope of this
invention. Such compounds are useful, for example, as analytical
tools or probes in biological assays.
[0058] The terms "stereoisomer", "enantiomer", "diastereomer",
"epimer", and "chiral center", are used herein in accordance with
the meaning each is given in ordinary usage by those of ordinary
skill in the art. Thus, stereoisomers are compounds that have the
same atomic connectivity, but differ in the spatial arrangement of
the atoms. Enantiomers are stereoisomers that have a mirror image
relationship, that is, the stereochemical configuration at all
corresponding chiral centers is opposite. Diastereomers are
stereoisomers having more than one chiral center, which differ from
one another in that the stereochemical configuration of at least
one, but not all, of the corresponding chiral centers is opposite.
Epimers are diastereomers that differ in stereochemical
configuration at only one chiral center.
[0059] It is to be understood that, when a disclosed compound has
at least one chiral center, the present invention encompasses one
enantiomer of the compound, substantially free from the
corresponding optical isomer, a racemic mixture of both optical
isomers of the compound, and mixtures enriched in one enantiomer
relative to its corresponding optical isomer. When a mixture is
enriched in one enantiomer relative to its optical isomer, the
mixture contains, for example, an enantiomeric excess of at least
50%, 75%, 90%, 95%, 99%, or 99.5%.
[0060] The enantiomers of the present invention may be resolved by
methods known to those skilled in the art, for example by formation
of diastereoisomeric salts which may be separated, for example, by
crystallization; formation of diastereoisomeric derivatives or
complexes which may be separated, for example, by crystallization,
gas-liquid or liquid chromatography; selective reaction of one
enantiomer with an enantiomer-specific reagent, for example
enzymatic esterification; or gas-liquid or liquid chromatography in
a chiral environment, for example on a chiral support for example
silica with a bound chiral ligand or in the presence of a chiral
solvent. Where the desired enantiomer is converted into another
chemical entity by one of the separation procedures described
above, a further step is required to liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0061] When a disclosed compound has at least two chiral centers,
the present invention encompasses a diastereomer substantially free
of other diastereomers, an enantiomeric pair of diastereomers
substantially free of other stereoisomers, mixtures of
diastereomers, mixtures of enantiomeric pairs of diastereomers,
mixtures of diastereomers in which one diastereomer is enriched
relative to the other diastereomer(s), and mixtures of enantiomeric
pairs of diastereomers in which one enantiomeric pair of
diastereomers is enriched relative to the other stereoisomers. When
a mixture is enriched in one diastereomer or enantiomeric pair of
diastereomers pairs relative to the other stereoisomers, the
mixture is enriched with the depicted or referenced diastereomer or
enantiomeric pair of diastereomers relative to other stereoisomers
for the compound, for example, by a molar excess of at least 50%,
75%, 90%, 95%, 99%, or 99.5%.
[0062] As used herein, the term "diastereomeric ratio" refers to
the ratio between diastereomers which differ in the stereochemical
configuration at one chiral center, relative to a second chiral
center in the same molecule. By way of example, a chemical
structure with two chiral centers provides four possible
stereoisomers: R*R, R*S, S*R, and S*S, wherein the asterisk denotes
the corresponding chiral center in each stereoisomer. The
diastereomeric ratio for such a mixture of stereoisomers is the
ratio of one diastereomer and its enantiomer to the other
diastereomer and its enantiomer=(R*R+S*S):(R*S+S*R).
[0063] One of ordinary skill in the art will recognize that
additional stereoisomers are possible when the molecule has more
than two chiral centers. For purposes of the present invention, the
term "diastereomeric ratio" has identical meaning in reference to
compounds with multiple chiral centers as it does in reference to
compounds having two chiral centers. Thus, the term "diastereomeric
ratio" refers to the ratio of all compounds having R*R or S*S
configuration at the specified chiral centers to all compounds
having R*S or S*R configuration at the specified chiral centers.
For convenience, this ratio is referred to herein as the
diastereomeric ratio at the asterisked carbon, relative to the
second specified chiral center.
[0064] The diastereomeric ratio can be measured by any analytical
method suitable for distinguishing between diastereomeric compounds
having different relative stereochemical configurations at the
specified chiral centers. Such methods include, without limitation,
nuclear magnetic resonance (NMR), gas chromatography (GC), and high
performance liquid chromatography (HPLC) methods.
[0065] The diastereoisomeric pairs may be separated by methods
known to those skilled in the art, for example chromatography or
crystallization and the individual enantiomers within each pair may
be separated as described above. Specific procedures for
chromatographically separating diastereomeric pairs of precursors
used in the preparation of compounds disclosed herein are provided
the examples herein.
3. Description of Exemplary Compounds
[0066] In some embodiments, the compound of formula (I) is
represented by:
##STR00005##
[0067] wherein R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1,
R.sup.2a, R.sup.2b, and G have the values described herein. In
certain embodiments, the compound of formula (I) is represented by
formula (I-a), wherein R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d,
R.sup.1, R.sup.2a, R.sup.2b, and G have the values described
herein. In certain embodiments, the compound of formula (I) is
represented by formula (I-b), wherein R.sup.1a, R.sup.1b, R.sup.1c,
R.sup.1d, R.sup.1, R.sup.2a, R.sup.2b, and G have the values
described herein. In certain embodiments, the compound of formula
(I) is represented by formula (I-c), wherein R.sup.1a, R.sup.1b,
R.sup.1c, R.sup.1d, R.sup.1, R.sup.2a, R.sup.2b, and G have the
values described herein.
[0068] In some embodiments, the compound of formula (I) is
represented by formula (II-a) or (II-b):
##STR00006##
[0069] wherein R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1,
X.sub.1, X.sub.2, and G have the values described herein.
[0070] In some embodiments, the compound of formula (I) is
represented by formula (II-a-i)-(II-b-iii):
##STR00007##
[0071] wherein R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1, and
G have the values described herein. In certain embodiments, the
compound of formula (I) is represented by formula (II-a-i), wherein
R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1, and G have the
values described herein. In certain embodiments, the compound of
formula (I) is represented by formula (II-a-ii), wherein R.sup.1a,
R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1, and G have the values
described herein. In certain embodiments, the compound of formula
(I) is represented by formula (II-b-i), wherein R.sup.1a, R.sup.1b,
R.sup.1c, R.sup.1d, R.sup.1, and G have the values described
herein.
[0072] In some embodiments, the compound of formula (I) is
represented by formula (III-a) or (III-b):
##STR00008##
[0073] wherein R.sup.1, X.sub.1, X.sub.2, and G have the values
described herein.
[0074] In some embodiments, the compound of formula (I) is
represented by formula (III-a-i)-(III-b-iii):
##STR00009##
[0075] wherein R.sup.1 and G have the values described herein. In
certain embodiments, the compound of formula (I) is represented by
formula (III-a-i), wherein R.sup.1 and G have the values described
herein. In certain embodiments, the compound of formula (I) is
represented by formula (III-a-ii), wherein R.sup.1 and G have the
values described herein. In certain embodiments, the compound of
formula (I) is represented by formula (III-b-i), wherein R.sup.1
and G have the values described herein.
[0076] In some embodiments, the compound of formula (I) is
represented by formula (IV-a) or (IV-b):
##STR00010##
[0077] wherein X.sub.1, X.sub.2, and G have the values described
herein.
[0078] In some embodiments, the compound of formula (I) is
represented by formula (IV-a-i)-(IV-b-iii):
##STR00011##
[0079] wherein G has the values described herein. In certain
embodiments, the compound of formula (I) is represented by formula
(IV-a-i), wherein G has the values described herein. In certain
embodiments, the compound of formula (I) is represented by formula
(IV-a-ii), wherein G has the values described herein. In certain
embodiments, the compound of formula (I) is represented by formula
(IV-b-i), wherein G has the values described herein.
[0080] The values described below for each variable are with
respect to any of formulas (I), (II), (III), (IV), or their
sub-formulas as described above.
[0081] The variable R.sup.1a is hydrogen, fluoro, C.sub.1-4 alkyl,
or C.sub.1-4 fluoroalkyl. In some embodiments, R.sup.1a is
hydrogen, fluoro, methyl, or trifluoromethyl. In certain
embodiments, R.sup.1a is hydrogen, fluoro, or methyl. In certain
embodiments, R.sup.1a is hydrogen.
[0082] The variable R.sup.1b is hydrogen, fluoro, C.sub.1-4 alkyl,
or C.sub.1-4 fluoroalkyl. In some embodiments, R.sup.1b is
hydrogen, fluoro, methyl, or trifluoromethyl. In certain
embodiments, R.sup.1b is hydrogen, fluoro, or methyl. In certain
embodiments, R.sup.1b is hydrogen.
[0083] In some embodiments, R.sup.1a and R.sup.1b are taken
together to form a 3-6 membered cycloaliphatic ring. In some
embodiments, R.sup.1a and R.sup.1b are taken together to form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain
embodiments, R.sup.1a and R.sup.1b are taken together to form
cyclopropyl.
[0084] In some embodiments, each occurrence of R.sup.1c is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; and each occurrence of R.sup.1d is independently
hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl. In
some embodiments, each occurrence of R.sup.1c is hydrogen, fluoro,
methyl, or trifluoromethyl. In some embodiments, each occurrence of
R.sup.1c is hydrogen, fluoro, or methyl. In certain embodiments,
each occurrence of R.sup.1c is hydrogen. In some embodiments, each
occurrence of R.sup.1d is hydrogen, fluoro, methyl, or
trifluoromethyl. In some embodiments, each occurrence of R.sup.1d
is hydrogen, fluoro, or methyl. In certain embodiments, each
occurrence of R.sup.1d is hydrogen.
[0085] In some embodiments, two occurrences of R.sup.1c are taken
together to form .dbd.O; and each occurrence of R.sup.1d is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl. In some embodiments, two occurrences of R.sup.1c are
taken together to form .dbd.O; and each occurrence of R.sup.1d is
independently hydrogen, fluoro, methyl, or trifluoromethyl. In some
embodiments, two occurrences of R.sup.1c are taken together to form
.dbd.O; and each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl. In some embodiments, two occurrences of R.sup.1c
are taken together to form .dbd.O; and each occurrence of R.sup.1d
is hydrogen.
[0086] In some embodiments, two occurrences of R.sup.1d are taken
together to form .dbd.O; and each occurrence of R.sup.1c is
independently hydrogen, fluoro, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl. In some embodiments, two occurrences of R.sup.1d are
taken together to form .dbd.O; and each occurrence of R.sup.1c is
independently hydrogen, fluoro, methyl, or trifluoromethyl. In some
embodiments, two occurrences of R.sup.1d are taken together to form
.dbd.O; and each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl. In some embodiments, two occurrences of R.sup.1d
are taken together to form .dbd.O; and each occurrence of R.sup.1c
is hydrogen.
[0087] Each occurrence of the variable R.sup.1 is independently
hydrogen, chloro, fluoro, --O--C.sub.1-4 alkyl, cyano, hydroxy,
C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl. In some embodiments,
each occurrence of R.sup.1 is independently hydrogen, chloro,
fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl, methyl,
or ethyl. In certain embodiments, each occurrence of R.sup.1 is
independently hydrogen, fluoro, or methyl. In certain embodiments,
each occurrence of R.sup.1 is hydrogen.
[0088] One of the variables X.sub.1 and X.sub.2 is CR.sup.1 and the
other is N; or both X.sub.1 and X.sub.2 are N, wherein R.sup.1 has
the values described herein. In some embodiments, X.sub.1 is
CR.sup.1 and X.sub.2 is N, wherein R.sup.1 has the values described
herein. In some embodiments, X.sub.1 is N and X.sub.2 is CR.sup.1,
wherein R.sup.1 has the values described herein. In some
embodiments, X.sub.1 is N and X.sub.2 is N.
[0089] One of the variable R.sup.2a and R.sup.2b is R.sup.1, and
the other is --C(O)--NH--OH, wherein R.sup.1 has the values
described herein. In some embodiments, R.sup.2a is R.sup.1 and
R.sup.2b is --C(O)--NH--OH, wherein R.sup.1 has the values
described herein. In some embodiments, R.sup.2b is R.sup.1 and
R.sup.2a is --C(O)--NH--OH, wherein R.sup.1 has the values
described herein.
[0090] The variable G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.2-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, --V.sub.1-L.sub.1-V.sub.2--R.sup.3, or
-L.sub.1-R.sup.3, wherein L.sub.1, V.sub.1, L.sub.2, V.sub.2, and
R.sup.3 have the values described herein. In some embodiments, G is
--R.sup.3, --V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or
-L.sub.1-R.sup.3, wherein L.sub.1, V.sub.1, and R.sup.3 have the
values described herein. In some embodiments, G is
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3,
wherein L.sub.1, V.sub.1, and R.sup.3 have the values described
herein. In certain embodiments, G is --V.sub.1--R.sup.3, wherein
V.sub.1 and R.sup.3 have the values described herein. In certain
embodiments, G is -L.sub.1-R.sup.3, wherein L.sub.1 and R.sup.3
have the values described herein. In certain embodiments, G is
--V.sub.1-L.sub.1-R.sup.3, wherein R.sup.3 has the values described
herein.
[0091] The variable L.sub.1 is an unsubstituted or substituted
C.sub.1-3 alkylene chain. In some embodiments, L.sub.1 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CR.sup.A.dbd.CR.sup.A, or --C.ident.C--. In some embodiments,
L.sub.1 is --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain embodiments, L.sub.1 is
--CH.sub.2--. In certain embodiments, L.sub.1 is
--CH.sub.2CH.sub.2--.
[0092] The variable L.sub.2 is an unsubstituted or substituted
C.sub.2-3 alkylene chain. In some embodiments, L.sub.2 is
--CH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2CH.sub.2--. In certain
embodiments, L.sub.2 is --CH.sub.2CH.sub.2--. In certain
embodiments, L.sub.2 is --CH.sub.2CH.sub.2CH.sub.2--.
[0093] Each occurrence of the variable R.sup.A is independently
hydrogen, fluoro, or unsubstituted or substituted C.sub.1-4
aliphatic. In some embodiments, each occurrence of R.sup.A is
independently hydrogen, fluoro or methyl. In certain embodiments,
each occurrence of R.sup.A is hydrogen.
[0094] The variable V.sub.1 is --C(O)--, --C(S)--,
--C(O)--N(R.sup.4a)--, --C(O)--O--, --S(O).sub.2--, or
--SO.sub.2--N(R.sup.4a)--; wherein R.sup.4a has the values
described herein. In some embodiments, V.sub.1 is --C(O)--,
--C(S)--, --C(O)--NH--, --C(O)--O--, --S(O).sub.2--, or
--SO.sub.2--NH--. In certain embodiments, V.sub.1 is --C(O)--,
--C(O)--N(R.sup.4a)--, or --S(O).sub.2-- wherein R.sup.4a has the
values described herein. In certain embodiments, V.sub.1 is
--C(O)--, --C(O)--NH--, or --S(O).sub.2.
[0095] The variable V.sub.2 is --N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--, --N(R.sup.4a)--SO.sub.2--,
--SO.sub.2--N(R.sup.4a)--, --SO.sub.2--, --C(O)--, --C(O)--O--,
--O--C(O)--, --O--, --S--, --N(R.sup.4a)--C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--O--, --O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--, wherein R.sup.4a has the
values described herein. In some embodiments, V.sub.2 is
--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--, --N(R.sup.4a)--SO.sub.2--,
--O--, --S--, --N(R.sup.4a)--C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--O--, --O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--, wherein R.sup.4a has the
values described herein. In some embodiments, V.sub.2 is
--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--, --N(R.sup.4a)--SO.sub.2--,
--SO.sub.2--N(R.sup.4a)--, --O--, or --S--, wherein R.sup.4a has
the values described herein. In certain embodiments, V.sub.2 is
--NH--, --NH--C(O)--, --NH--SO.sub.2--, --SO.sub.2--NH--, --O--, or
--S--. In certain embodiments, V.sub.2 is --N(R.sup.4a)--, --O--,
or --S--, wherein R.sup.4a has the values described herein. In
certain embodiments, V.sub.2 is --NH--, --O--, or --S--.
[0096] Each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic. In certain
embodiments, each occurrence of R.sup.4a is hydrogen.
[0097] The variable R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur.
[0098] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein:
[0099] each substitutable carbon chain atom in R.sup.3 is
unsubstituted or substituted with 1-2 occurrences of
--R.sup.5dd;
[0100] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.C(R.sup.5).sub.2, or
--R.sup.5aa;
[0101] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0102] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0103] wherein R.sup.5dd, R.sup.5, R.sup.5a, R.sup.5aa, and
R.sup.9b have the values described herein.
[0104] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein:
[0105] each substitutable carbon chain atom in R.sup.3 is
unsubstituted or substituted with 1-2 occurrences of
--R.sup.5dd;
[0106] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with R.sup.5aa;
[0107] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0108] the total number of R.sup.5a and R.sup.5aa substituents is
p; and
[0109] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0110] wherein R.sup.5dd, R.sup.5a, R.sup.9b and p have the values
described herein.
[0111] Each occurrence of the variable R.sup.5dd is independently
fluoro, hydroxy, --O(C.sub.1-6 alkyl), cyano, --N(R.sup.4).sub.2,
--C(O)(C.sub.1-6 alkyl), --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6 alkyl).sub.2,
--NHC(O)C.sub.1-6 alkyl, --NHC(O)OC.sub.1-6 alkyl,
--NHC(O)NHC.sub.1-6 alkyl, or --NHS(O).sub.2C.sub.1-6 alkyl,
wherein R.sup.4 has the values described herein. In some
embodiments, each occurrence of R.sup.5dd is independently fluoro,
hydroxy, methoxy, ethoxy, --NH(C.sub.1-6 alkyl), --N(C.sub.1-6
alkyl).sub.2, or --C(O)NHCH.sub.3.
[0112] Each occurrence of the variable R.sup.9b is independently
--C(O)R.sup.6, --C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, unsubstituted
C.sub.3-10 cycloaliphatic, C.sub.3-10 cycloaliphatic substituted
with 1-2 independent occurrences of R.sup.7 or R.sup.8,
unsubstituted C.sub.1-6 aliphatic, or C.sub.1-6 aliphatic
substituted with 1-2 independent occurrences of R.sup.7 or R.sup.8,
wherein R.sup.7 and R.sup.8 have the values described herein. In
some embodiments, each occurrence of R.sup.9b is independently
unsubstituted --C(O)--C.sub.1-6 aliphatic, unsubstituted
--C(O)--C.sub.3-10 cycloaliphatic, or unsubstituted C.sub.1-6
aliphatic. In some embodiments, each occurrence of R.sup.9b is
unsubstituted C.sub.1-6 aliphatic. In certain embodiments, each
occurrence of R.sup.9b is independently methyl, ethyl, isopropyl,
isobutyl, n-propyl, n-butyl, tert-butyl, --C(O)-methyl,
--C(O)-ethyl, --C(O)-cyclopropyl, --C(O)-tert-butyl,
--C(O)-isopropyl, or --C(O)-cyclobutyl. In certain embodiments,
each occurrence of R.sup.9b is independently methyl, ethyl,
isopropyl, isobutyl, n-propyl, n-butyl, or tert-butyl.
[0113] Each occurrence of the variable R.sup.4 is independently
hydrogen, unsubstituted or substituted C.sub.1-6 aliphatic,
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; or two R.sup.4 on the same nitrogen atom, taken together
with the nitrogen atom, form an unsubstituted or substituted 5- to
6-membered heteroaryl or an unsubstituted or substituted 4- to
8-membered heterocyclyl having, in addition to the nitrogen atom,
0-2 ring heteroatoms selected from nitrogen, oxygen, and
sulfur.
[0114] Each occurrence of the variable R.sup.5 is independently
hydrogen, unsubstituted or substituted C.sub.1-6 aliphatic,
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[0115] Each occurrence of the variable R.sup.6 is independently
unsubstituted or substituted C.sub.1-6 aliphatic, unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0116] Each occurrence of the variable R.sup.7 is independently
unsubstituted or substituted 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[0117] Each occurrence of the variable R.sup.8 is independently
chloro, fluoro, --OH, --O(C.sub.1-6 alkyl), --CN,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-6 alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-6
alkyl), or --C(O)N(C.sub.1-6 alkyl).sub.2, wherein R.sup.4 has the
values described herein.
[0118] Each occurrence of the variable R.sup.5a is independently
halogen, --NO.sub.2, --CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C.ident.C--R.sup.5, --OR.sup.5, --SR.sup.6, --S(O)R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2, --C(O)R.sup.6,
--C(O)N(R.sup.4).sub.2, --N(R.sup.4)SO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2N(R.sup.4).sub.2, unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; or two adjacent R.sup.5a, taken
together with the intervening ring atoms, form an unsubstituted or
substituted fused 5-10 membered aromatic ring or an unsubstituted
or substituted 4-10 membered non-aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, wherein R.sup.5, R.sup.6, and R.sup.4 have the values
described herein.
[0119] In some embodiments, each occurrence of R.sup.5a is
independently halogen, cyano, nitro, hydroxy, unsubstituted
C.sub.1-6 aliphatic, C.sub.1-6 aliphatic substituted with 1-2
independent occurrences of R.sup.7 or R.sup.8, unsubstituted
O--C.sub.1-6 alkyl, --O--C.sub.1-6 alkyl substituted with 1-2
independent occurrences of R.sup.7 or R.sup.8, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 fluoroalkyl, --NHC(O)R.sup.6,
--C(O)NH(R.sup.4), --NHC(O)O--C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6
alkyl, --NHS(O).sub.2C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, 3-10-membered cycloaliphatic
substituted with 0-2 occurrences of --R.sup.7a, 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of
R.sup.7a, 6-10-membered aryl substituted with 0-2 occurrences of
R.sup.7a, or 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur
substituted with 0-2 occurrences of --R.sup.7a, wherein R.sup.4,
R.sup.5, R.sup.7a, R.sup.7, and R.sup.8 have the values described
herein.
[0120] In certain embodiments, each occurrence of R.sup.5a is
independently chloro, fluoro, hydroxy, methoxy, ethoxy, cyano,
trifluoromethyl, methyl, ethyl, isopropyl, --NHC(O)-tert-butyl,
--NHC(O)-cyclopropyl, --NHC(O)R.sup.10, --C(O)NHR.sup.10,
--CH.sub.2--N(R.sup.4).sub.2 or --NHSO.sub.2CH.sub.3, wherein
R.sup.10 has the values described herein.
[0121] Each occurrence of the variable R.sup.10 is unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur. In some
embodiments, each occurrence of R.sup.10 is unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, wherein
if substituted R.sup.10 is substituted with 0-2 occurrences of
--R.sup.7aa, wherein R.sup.7aa has the values described herein. In
some embodiments, each occurrence of R.sup.10 is pyrrolidinyl,
piperidinyl, pyrrolinyl, piperazinyl, or morpholinyl, wherein each
of the foregoing groups is unsubstituted or substituted with 0-1
occurrence of R.sup.7aa, wherein R.sup.7aa has the values described
herein.
[0122] Each occurrence of the variable R.sup.5aa is independently
chloro, fluoro, hydroxy, unsubstituted or substituted C.sub.1-6
aliphatic, --O(C.sub.1-6 alkyl), --C.sub.1-6 fluoroalkyl,
--O--C.sub.1-6 fluoroalkyl, cyano, --N(R.sup.4).sub.2,
--C(O)(C.sub.1-6 alkyl), --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6 alkyl).sub.2,
--NHC(O)C.sub.1-6 alkyl, --NHC(O)OC.sub.1-6 alkyl,
--NHC(O)NHC.sub.1-6 alkyl, --NHC(O)N(C.sub.1-6 alkyl).sub.2, or
--NHS(O).sub.2C.sub.1-6 alkyl. In some embodiments, each occurrence
of R.sup.5aa is independently chloro, fluoro, hydroxy, methyl,
ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy,
--C(O)NH.sub.2, alkyl).sub.2, --NHC.sub.1-6 alkyl, or --CO.sub.2H.
In certain embodiments, each occurrence of R.sup.5aa is
independently fluoro, methyl, ethyl, methoxy, ethoxy,
--C(O)NH.sub.2, --N(C.sub.1-6 alkyl).sub.2, --NHC.sub.1-6 alkyl, or
--CO.sub.2H.
[0123] Each occurrence of the variable R.sup.7a is independently
chloro, fluoro, C.sub.1-6 aliphatic, C.sub.1-6 fluoroalkyl,
--O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl, cyano, hydroxy,
--CO.sub.2H, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
[0124] Each occurrence of the variable R.sup.7aa is independently
chloro, fluoro, hydroxy, unsubstituted or substituted C.sub.1-6
aliphatic, --O(C.sub.1-6 alkyl), --C.sub.1-6 fluoroalkyl,
--O--C.sub.1-6 fluoroalkyl, cyano, --N(R.sup.4).sub.2,
--C(O)(C.sub.1-6 alkyl), --CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6 alkyl).sub.2,
--NHC(O)C.sub.1-6 alkyl, --NHC(O)OC.sub.1-6 alkyl,
--NHC(O)NHC.sub.1-6 alkyl, --NHC(O)N(C.sub.1-6alkyl).sub.2, or
--NHS(O).sub.2C.sub.1-6 alkyl. In some embodiments, each occurrence
of R.sup.7aa is independently fluoro, hydroxy, methyl, ethyl,
methoxy, trifluoromethyl, --C(O)NH.sub.2, or --CO.sub.2H.
[0125] The variable p is 1-4. In some embodiments, p is 1-3. In
certain embodiments, p is 1-2. In certain embodiments, p is 1.
[0126] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic. In some embodiments, each substitutable carbon
chain atom in R.sup.3 is unsubstituted or substituted with 1-2
occurrences of --R.sup.5dd, wherein R.sup.5dd has the values
described herein. In certain embodiments, R.sup.3 is methyl, ethyl,
n-propyl, isopropyl, tert-butyl, n-butyl, iso-butyl, pentyl, hexyl,
butenyl, propenyl, pentenyl, or hexenyl, wherein each of the
forementioned groups is unsubstituted or substituted. In certain
embodiments, R.sup.3 is methyl, ethyl, n-propyl, isopropyl,
tert-butyl, n-butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl,
pentenyl, or hexenyl, wherein each substitutable carbon chain atom
in R.sup.3 is unsubstituted or substituted with 1-2 occurrences of
--R.sup.5dd, wherein R.sup.5dd has the values described herein.
[0127] In some embodiments, R.sup.3 is unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur.
[0128] In certain embodiments, R.sup.3 is unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
wherein:
[0129] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.C(R.sup.5).sub.2, or
--R.sup.5aa;
[0130] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0131] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0132] wherein R.sup.5, R.sup.5a, R.sup.5aa, and R.sup.9b have the
values described herein.
[0133] In certain embodiments, R.sup.3 is unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
wherein:
[0134] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5aa;
[0135] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0136] the total number of R.sup.5a and R.sup.5aa substituents is
p; and
[0137] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0138] wherein R.sup.5a, R.sup.5aa, R.sup.9b and p have the values
described herein.
[0139] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl,
indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,
tetrahydroquinolinyl, tetrahydronaphthyridinyl,
tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydropyranyl,
tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,
quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,
benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, azabicyclooctanyl,
oxabicyclooctanyl, bicyclononyl, bicyclooctanyl, or adamantyl;
wherein:
[0140] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.C(R.sup.5).sub.2, or
R.sup.5aa;
[0141] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0142] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0143] wherein R.sup.5, R.sup.5a, R.sup.5aa, and R.sup.9b have the
values described herein.
[0144] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl,
indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,
tetrahydroquinolinyl, tetrahydronaphthyridinyl,
tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,
quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,
benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, azabicyclooctanyl,
oxabicyclooctanyl, bicyclononyl, bicyclooctanyl, or adamantyl;
wherein:
[0145] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5aa;
[0146] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0147] the total number of R.sup.5a and R.sup.5aa substituents is
p; and
[0148] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0149] wherein R.sup.5a, R.sup.5aa, R.sup.9b, and p have the values
described herein.
[0150] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or
triazinyl; wherein:
[0151] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or substituted with --R.sup.5a;
[0152] each occurrence of R.sup.5a is independently chloro, fluoro,
hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, methyl, ethyl,
isopropyl, --NHC(O)-tert-butyl, --NHC(O)-cyclopropyl,
--NHC(O)R.sup.10, --C(O)NHR.sup.10, --CH.sub.2--N(R.sup.4).sub.2,
or --NHSO.sub.2CH.sub.3;
[0153] the total number of R.sup.5a substituents is p;
[0154] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b; and
[0155] each occurrence of R.sup.9b is independently methyl, ethyl,
isopropyl, isobutyl, n-propyl, n-butyl, or tert-butyl;
[0156] wherein p and R.sup.10 have the values described herein.
[0157] In certain embodiments, R.sup.3 is indolizinyl,
imidazopyridyl, indolyl, indazolyl, benzimidazolyl, benzthiazolyl,
benzothienyl, benzofuranyl, benzoxazolyl, benzthiadiazolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, naphthyl,
or pteridinyl; wherein:
[0158] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or substituted with --R.sup.5a;
[0159] each occurrence of R.sup.5a is independently chloro, fluoro,
hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, methyl, ethyl,
isopropyl, --NHC(O)-tert-butyl, --NHC(O)-cyclopropyl,
--NHC(O)R.sup.10, --C(O)NHR.sup.10, --CH.sub.2--N(R.sup.4).sub.2,
or --NHSO.sub.2CH.sub.3;
[0160] the total number of R.sup.5a substituents is p;
[0161] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b; and
[0162] each R.sup.9b is independently methyl, ethyl, isopropyl,
isobutyl, n-propyl, n-butyl, or tert-butyl;
[0163] wherein p and R.sup.10 have the values described herein.
[0164] In certain embodiments, R.sup.3 is tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,
piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, or
cyclooctenyl; wherein:
[0165] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5aa;
[0166] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0167] the total number of R.sup.5a and R.sup.5aa substituents is
p;
[0168] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0169] each occurrence of R.sup.5a is independently chloro, fluoro,
hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, methyl, ethyl,
isopropyl, --NHC(O)-tert-butyl, --NHC(O)-cyclopropyl,
--NHC(O)R.sup.10, --C(O)NHR.sup.10, --CH.sub.2--N(R.sup.4).sub.2,
or --NHSO.sub.2CH.sub.3;
[0170] each occurrence of R.sup.5aa is independently chloro,
fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,
trifluromethoxy, --C(O)NH.sub.2, --N(C.sub.1-6 alkyl).sub.2,
--NHC.sub.1-6 alkyl, or --CO.sub.2H; and
[0171] each R.sup.9b is independently methyl, ethyl, isopropyl,
isobutyl, n-propyl, n-butyl, tert-butyl, --C(O)-methyl,
--C(O)-ethyl, --C(O)-cyclopropyl, --C(O)-tert-butyl,
--C(O)-isopropyl, or --C(O)-cyclobutyl;
[0172] wherein R.sup.10 and p have the values described herein.
[0173] In certain embodiments, R.sup.3 is pyrrolidinyl,
piperidinyl, or piperazinyl; wherein:
[0174] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5aa;
[0175] the total number of R.sup.5aa substituents is p; and
[0176] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0177] wherein R.sup.5aa, p, and R.sup.9b have the values described
herein.
[0178] In certain embodiments, R.sup.3 is pyrrolidinyl,
piperidinyl, or piperazinyl; wherein:
[0179] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with R.sup.5aa;
[0180] the total number of R.sup.5aa substituents is p;
[0181] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0182] each occurrence of R.sup.5aa is independently chloro,
fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,
trifluromethoxy, --C(O)NH.sub.2, --N(C.sub.1-6 alkyl).sub.2,
--NHC.sub.1-6 alkyl, or --CO.sub.2H;
[0183] each occurrence of R.sup.9b is independently methyl, ethyl,
isopropyl, isobutyl, n-propyl, n-butyl, tert-butyl, --C(O)-methyl,
--C(O)-ethyl, --C(O)-cyclopropyl, --C(O)-tert-butyl,
--C(O)-isopropyl, or --C(O)-cyclobutyl; and
[0184] p is 1-2.
[0185] In certain embodiments, R.sup.3 is tetrahydroindazolyl,
bicycloheptanyl, azabicyclooctanyl, oxabicyclooctanyl,
bicyclononyl, bicyclooctanyl, adamantyl, isoindolyl, benzodioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, quinuclidinyl,
tetrahydroquinolinyl, tetrahydronaphthyridinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, tetrahydronaphthyl,
indolinyl, benzodioxanyl, chromanyl, tetrahydroindazolyl, or
indanyl; wherein:
[0186] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5aa;
[0187] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a;
[0188] the total number of R.sup.5a and R.sup.5aa substituents is
p;
[0189] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0190] each occurrence of R.sup.5a is independently chloro, fluoro,
hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, methyl, ethyl,
isopropyl, --NHC(O)-tert-butyl, --NHC(O)-cyclopropyl,
--NHC(O)R.sup.10, --C(O)NHR.sup.10, --CH.sub.2--N(R.sup.4).sub.2,
or --NHSO.sub.2CH.sub.3;
[0191] each occurrence of R.sup.5aa is independently chloro,
fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,
trifluromethoxy, --C(O)NH.sub.2, --N(C.sub.1-6 alkyl).sub.2,
--NHC.sub.1-6 alkyl, or --CO.sub.2H; and
[0192] each R.sup.9b is independently methyl, ethyl, isopropyl,
isobutyl, n-propyl, n-butyl, tert-butyl, --C(O)-methyl,
--C(O)-ethyl, --C(O)-cyclopropyl, --C(O)-tert-butyl,
--C(O)-isopropyl, or --C(O)-cyclobutyl;
[0193] wherein R.sup.10 and p have the values described herein.
[0194] In some embodiments, G is:
##STR00012##
[0195] wherein X and Ring C have the values described herein.
[0196] In certain embodiments, G is:
##STR00013##
[0197] wherein Ring C has the values described herein.
[0198] The variable X is --C(O)-- or
L.sub.2a-R.sup.3aa--V.sub.2a--, wherein L.sub.2a, R.sup.3aa, and
V.sub.2a have the values described herein. In some embodiments, X
is --C(O)--. In some embodiments, X is
L.sub.2a-R.sup.3aa--V.sub.2a--, wherein L.sub.2a, R.sup.3aa, and
V.sub.2a have the values described herein. In some embodiments, X
is --C(O)--,
##STR00014##
wherein V.sub.2a and t have the values described herein.
[0199] In certain embodiments, X is --C(O)--,
##STR00015## ##STR00016## ##STR00017##
[0200] In certain embodiments, X is --C(O)--, X-ii, X-iii, X-xi,
X-xii, X-xxii, X-xxiv, or X-xxv.
[0201] Ring C is a 4-7 membered heterocyclic ring containing one
nitrogen atom, wherein the nitrogen atom is not the atom bound to
X, and wherein the nitrogen atom in Ring C is substituted with
R.sup.9bb and Ring C is unsubstituted or substituted by 1-4
occurrences of R.sup.5b; wherein R.sup.9bb, X, and R.sup.5b have
the values described herein. In some embodiments, Ring C is a 4-7
membered heterocyclic ring containing one nitrogen atom, wherein
the nitrogen atom is not the atom bound to X, and wherein the
nitrogen atom in Ring C is substituted with R.sup.9bb and Ring C is
unsubstituted or substituted by 1-2 occurrences of R.sup.5b;
wherein R.sup.9bb, X, and R.sup.5b have the values described
herein.
[0202] In certain embodiments, Ring C is:
##STR00018##
[0203] wherein Ring C is unsubstituted or substituted with 1
occurrence of R.sup.5b, wherein R.sup.9bb and R.sup.5b have the
values described herein. In certain embodiments, Ring C is:
##STR00019##
[0204] wherein R.sup.9bb, z and R.sup.5bb have the values described
herein.
[0205] The variable V.sub.2a is a bond, --NH--C(O)--,
--NH--S(O).sub.2--, or --NH--C(O)--NH--. In some embodiments,
V.sub.2a is a bond or --NH--C(O)--. In certain embodiments,
V.sub.2a is a bond. In certain embodiments, V.sub.2a is
--NH--C(O)--.
[0206] The variable t is 0-2. In some embodiments, t is 0-1. In
certain embodiments, t is 0. In certain embodiments, t is 1. In
certain embodiments, t is 2.
[0207] The variable L.sub.2a is a bond or unsubstituted or
substituted C.sub.1-3 alkylene chain. In some embodiments, L.sub.2a
is a bond, --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain embodiments, L.sub.2a is a
bond. In certain embodiments, L.sub.2a is --CH.sub.2--. In certain
embodiments, L.sub.2a is --CH.sub.2CH.sub.2--.
[0208] The variable R.sup.3aa is a 6-membered aromatic ring
containing 0-2 nitrogen atoms which is unsubstituted or substituted
with 1-2 independent occurrences of R.sup.4c, wherein R.sup.4c has
the values described herein. In some embodiments, R.sup.3aa is
phenyl or pyridyl, each of which is unsubstituted or substituted
with 1-2 independent occurrences of R.sup.4c, wherein R.sup.4c has
the values described herein. In some embodiments, R.sup.3aa is:
##STR00020##
[0209] wherein each ring is unsubstituted or substituted with 1-2
independent occurrences of R.sup.4c.
[0210] The variable R.sup.4c is chloro, fluoro, cyano, hydroxy,
methoxy, ethoxy, trifluoromethoxy, trifluoromethyl, methyl, or
ethyl. In some embodiments, R.sup.4c is chloro, fluoro, methyl or
ethyl.
[0211] The variable z is 0-1. In some embodiments, z is 0. In some
embodiments, z is 1.
[0212] Each occurrence of the variable R.sup.5b is independently
chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, trifluoromethoxy, --C(O)NH.sub.2, or --CO.sub.2H.
In some embodiments, each occurrence of the variable R.sup.5b is
independently chloro, fluoro, hydroxy, methyl, or ethyl. In certain
embodiments, each occurrence of the variable R.sup.5b is
methyl.
[0213] The variable R.sup.5bb is hydrogen or methyl. In some
embodiments, R.sup.5bb is hydrogen. In some embodiments, R.sup.5bb
is methyl.
[0214] The variable R.sup.9bb is hydrogen, unsubstituted
C(O)--O--C.sub.1-6 aliphatic, unsubstituted C(O)--C.sub.1-6
aliphatic, unsubstituted C(O)--C.sub.3-10 cycloaliphatic, or
unsubstituted C.sub.1-6 aliphatic. In some embodiments, R.sup.9bb
is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl. In
some embodiments, R.sup.9bb is methyl, ethyl, or isopropyl. In
certain embodiments, R.sup.9bb is hydrogen.
[0215] In certain embodiments for the compounds of formulas (I),
(II), (III) and (IV):
[0216] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3; and
[0217] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
[0218] In certain embodiments for the compounds of formulas (I),
(II), (III) and (IV):
[0219] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0220] L.sub.1 is --CH.sub.2-- or --CH.sub.2CH.sub.2--; and
[0221] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--.
[0222] In certain embodiments, for the compound of formula (I):
[0223] R.sup.1a is hydrogen, fluoro, or methyl;
[0224] R.sup.1b is hydrogen, fluoro, or methyl;
[0225] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl; and
[0226] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl.
[0227] In certain embodiments, the compound of formula (I) is
represented by:
##STR00021##
[0228] wherein:
[0229] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0230] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--;
[0231] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0232] R.sup.1a is hydrogen, fluoro, or methyl;
[0233] R.sup.1b is hydrogen, fluoro, or methyl;
[0234] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl; and
[0235] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0236] wherein R.sup.3 and R.sup.4a have the values contained
herein.
[0237] In certain embodiments, the compound of formula (I) is
represented by:
##STR00022##
[0238] wherein:
[0239] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0240] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--;
[0241] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0242] R.sup.1a is hydrogen, fluoro, or methyl;
[0243] R.sup.1b is hydrogen, fluoro, or methyl;
[0244] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl; and
[0245] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0246] wherein R.sup.3 and R.sup.4a have the values contained
herein.
[0247] In certain embodiments, the compound of formula (I) is
represented by:
##STR00023##
[0248] wherein:
[0249] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0250] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--;
[0251] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0252] R.sup.1a is hydrogen, fluoro, or methyl;
[0253] R.sup.1b is hydrogen, fluoro, or methyl;
[0254] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl; and
[0255] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0256] wherein R.sup.3 and R.sup.4a have the values contained
herein.
[0257] In certain embodiments, the compound of formula (I) is
represented by:
##STR00024##
wherein:
[0258] one of X.sub.1 and X.sub.2 is CR.sup.1 and the other is N;
or both X.sub.1 and X.sub.2 are N;
[0259] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0260] R.sup.1a is hydrogen, fluoro, or methyl;
[0261] R.sup.1b is hydrogen, fluoro, or methyl;
[0262] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl;
[0263] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl; and
[0264] X and Ring C have the values described herein.
[0265] In certain such embodiments:
[0266] R.sup.1a is hydrogen;
[0267] R.sup.1b is hydrogen;
[0268] R.sup.1c is hydrogen;
[0269] R.sup.1d is hydrogen; and
[0270] R.sup.1 is hydrogen.
[0271] In certain embodiments, the compound of formula (I) is
represented by:
##STR00025##
wherein:
[0272] one of X.sub.1 and X.sub.2 is CR.sup.1 and the other is N;
or both X.sub.1 and X.sub.2 are N;
[0273] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0274] R.sup.1a is hydrogen, fluoro, or methyl;
[0275] R.sup.1b is hydrogen, fluoro, or methyl;
[0276] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl;
[0277] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl; and
[0278] X and Ring C have the values described herein.
[0279] In certain such embodiments:
[0280] R.sup.1a is hydrogen;
[0281] R.sup.1b is hydrogen;
[0282] R.sup.1c is hydrogen;
[0283] R.sup.1d is hydrogen; and
[0284] R.sup.1 is hydrogen.
[0285] In certain embodiments, the compound of formula (I) is
represented by:
##STR00026##
wherein:
[0286] one of X.sub.1 and X.sub.2 is CR.sup.1 and the other is N;
or both X.sub.1 and X.sub.2 are N;
[0287] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0288] R.sup.1a is hydrogen, fluoro, or methyl;
[0289] R.sup.1b is hydrogen, fluoro, or methyl;
[0290] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl;
[0291] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0292] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0293] X is --C(O)--, X-a, X-b, X-c, X-d, X-e, X-f, or X-g;
[0294] Ring C is unsubstituted or substituted with one occurrence
of R.sup.5b; and
[0295] z, R.sup.5b, t, and V.sub.2 have the values described
herein.
[0296] In certain such embodiments,
[0297] R.sup.5b is methyl;
[0298] R.sup.1a is hydrogen;
[0299] R.sup.1b is hydrogen;
[0300] R.sup.1c is hydrogen;
[0301] R.sup.1d is hydrogen; and
[0302] R.sup.1 is hydrogen.
[0303] In certain embodiments, the compound of formula (I) is
represented by:
##STR00027##
wherein:
[0304] one of X.sub.1 and X.sub.2 is CR.sup.1 and the other is N;
or both X.sub.1 and X.sub.2 are N;
[0305] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0306] R.sup.1a is hydrogen, fluoro, or methyl;
[0307] R.sup.1b is hydrogen, fluoro, or methyl;
[0308] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl;
[0309] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0310] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0311] X is --C(O)--, X-a, X-b, X-c, X-d, X-e, X-f, or X-g;
[0312] Ring C is unsubstituted or substituted with one occurrence
of R.sup.5b; and
[0313] z, R.sup.5b, t, and V.sub.2 have the values described
herein.
[0314] In certain such embodiments,
[0315] R.sup.5b is methyl;
[0316] R.sup.1a is hydrogen;
[0317] R.sup.1b is hydrogen;
[0318] R.sup.1c is hydrogen;
[0319] R.sup.1d is hydrogen; and
[0320] R.sup.1 is hydrogen.
[0321] In certain embodiments, the compound of formula (I) is
represented by:
##STR00028##
[0322] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0323] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0324] X is --C(O)--, X-ii, X-iii, X-xi, X-xii, X-xxii, X-xxiv, or
X-xxv;
[0325] R.sup.5bb is hydrogen or methyl; and
[0326] z has the values described herein.
[0327] In certain such embodiments:
[0328] R.sup.1 is hydrogen
[0329] R.sup.5bb is methyl; and
[0330] z is 1.
[0331] In certain embodiments, the compound of formula (I) is
represented by:
##STR00029##
[0332] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0333] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0334] X is --C(O)--, X-ii, X-iii, X-xi, X-xii, X-xxii, X-xxiv, or
X-xxv;
[0335] R.sup.5bb is hydrogen or methyl; and
[0336] z has the values described herein.
[0337] In certain such embodiments:
[0338] R.sup.1 is hydrogen;
[0339] R.sup.5bb is methyl; and
[0340] z is 1.
[0341] In certain embodiments, the compound of formula (I) is
represented by:
##STR00030##
[0342] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0343] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0344] X is --C(O)--, X-ii, X-iii, X-xi, X-xii, X-xxii, X-xxiv, or
X-xxv;
[0345] R.sup.5bb is hydrogen or methyl; and
[0346] z has the values described herein.
[0347] In certain such embodiments:
[0348] R.sup.1 is hydrogen;
[0349] R.sup.5bb is methyl; and
[0350] z is 1.
[0351] In some embodiments, the compound of formula (I) is
represented by formula (II-a-i)-(II-b-iii):
##STR00031##
[0352] wherein:
[0353] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0354] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or
--S(O).sub.2--;
[0355] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0356] R.sup.1a is hydrogen, fluoro, or methyl;
[0357] R.sup.1b is hydrogen, fluoro, or methyl;
[0358] each occurrence of R.sup.1c is independently hydrogen,
fluoro, or methyl; and
[0359] each occurrence of R.sup.1d is independently hydrogen,
fluoro, or methyl;
[0360] wherein R.sup.3, L.sub.1, and R.sup.4a have the values
contained herein.
[0361] In certain such embodiments, the compound of formula (I) is
represented by formula (II-a-i). In certain such embodiments, the
compound of formula (I) is represented by formula (II-a-ii). In
certain such embodiments, the compound of formula (I) is
represented by formula (II-a-iii). In certain such embodiments, the
compound of formula (I) is represented by formula (II-b-i). In
certain such embodiments, the compound of formula (I) is
represented by formula (II-b-ii). In certain such embodiments, the
compound of formula (I) is represented by formula (II-b-iii).
[0362] In some embodiments, the compound of formula (I) is
represented by formula (III-a-i)-(III-b-iii):
##STR00032##
[0363] wherein:
[0364] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, or -L.sub.1-R.sup.3;
[0365] V.sub.1 is --C(O)--, --C(O)--NH--, or --S(O).sub.2;
[0366] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, cyano, hydroxy, methoxy, ethoxy, trifluoromethyl,
methyl, or ethyl;
[0367] wherein R.sup.3 and L.sub.1 have the values described
herein.
[0368] In certain such embodiments, the compound of formula (I) is
represented by formula (III-a-i). In certain such embodiments, the
compound of formula (I) is represented by formula (III-a-ii). In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-iii). In certain such embodiments,
the compound of formula (I) is represented by formula (III-b-i). In
certain such embodiments, the compound of formula (I) is
represented by formula (III-b-ii). In certain such embodiments, the
compound of formula (I) is represented by formula (III-b-iii).
[0369] In certain such embodiments, the compound of formula (I) is
represented by formula (III-a-i) wherein R.sup.1 is hydrogen; and
L.sub.1 is --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain such embodiments, the
compound of formula (I) is represented by formula (III-a-ii)
wherein R.sup.1 is hydrogen; and L.sub.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, or --CH.sub.2CH.sub.2CH.sub.2--. In certain
such embodiments, the compound of formula (I) is represented by
formula (III-a-iii) wherein R.sup.1 is hydrogen; and L.sub.1 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain such embodiments, the
compound of formula (I) is represented by formula (III-b-i) wherein
R.sup.1 is hydrogen; and L.sub.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, or --CH.sub.2CH.sub.2CH.sub.2--. In certain
such embodiments, the compound of formula (I) is represented by
formula (III-b-ii) wherein R.sup.1 is hydrogen; and L.sub.1 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain such embodiments, the
compound of formula (I) is represented by formula (III-b-iii)
wherein R.sup.1 is hydrogen; and L.sub.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, or --CH.sub.2CH.sub.2CH.sub.2--.
[0370] Representative examples of compounds of formula (I) are
shown in Table 1:
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054##
[0371] The compounds in Table 1 above may also be identified by the
following chemical names:
TABLE-US-00001 I-1
N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-5,6,7,8-tetrahydro--
1,6-naphthyridine-3- carboxamide I-2
6-acetyl-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide
I-3 tert-butyl
3-[(hydroxyamino)carbonyl]-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylat-
e I-4
7-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthy-
ridine-3-carboxamide I-5
6-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-5,6,7,8-tetrahydro--
1,6-naphthyridine-3- carboxamide I-6
N-hydroxy-6-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-5,6,7-
,8-tetrahydro-1,6- naphthyridine-2-carboxamide I-7
N-hydroxy-6-[(3-phenyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,6--
naphthyridine-2- carboxamide I-8
N.sup.2-hydroxy-N.sup.6-(2-methylphenyl)-7,8-dihydro-1,6-naphthyridine-
-2,6(5H)-dicarboxamide I-9
N-hydroxy-7-[(1-methylcyclohexyl)carbonyl]-5,6,7,8-tetrahydro-1,7-naph-
thyridine-3- carboxamide I-10
N-hydroxy-7-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-5,6,7,8-tetrahydro--
1,7-naphthyridine-3- carboxamide I-11
N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,-
6-naphthyridine-2- carboxamide I-12
6-(4-chlorobenzoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3--
carboxamide I-13
N.sup.6-[1-adamantyl]-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2-
,6(5H)-dicarboxamide I-14
6-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphth-
yridine-2-carboxamide I-15
7-[1-adamantylcarbonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-
e-3-carboxamide I-16
N.sup.6-(sec-butyl)-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6-
(5H)-dicarboxamide I-17
N.sup.6-cyclohexyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(-
5H)-dicarboxamide I-18
7-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphth-
yridine-3-carboxamide I-19
N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-5,6,7,8-tetrahydro-1,6-nap-
hthyridine-2- carboxamide I-20
6-benzyl-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxamide
I-21
7-acetyl-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide
I-22
6-[1-adamantylcarbonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridin-
e-2-carboxamide I-23
N-hydroxy-6-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-5,6,-
7,8-tetrahydro-1,6- naphthyridine-3-carboxamide I-24
N-hydroxy-7-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,-
7-naphthyridine-3- carboxamide I-25
N.sup.6-benzyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5H)--
dicarboxamide I-26
N-hydroxy-7-[(3-hydroxy-1-adamantyl)carbonyl]-5,6,7,8-tetrahydro-1,7--
naphthyridine-3- carboxamide I-27
N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-5,6,7,8-tetrahydro--
1,6-naphthyridine-2- carboxamide I-28
7-(4-chlorobenzoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3--
carboxamide I-29
N-hydroxy-6-[(3-phenyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,6-
-naphthyridine-3- carboxamide I-30
6-(2,2-dimethylpropanoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyrid-
ine-3-carboxamide I-31
6-[1-adamantylcarbonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridin-
e-3-carboxamide I-32
N-hydroxy-6-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-
-carboxamide I-33
6-(4-chlorobenzoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2--
carboxamide I-34
N.sup.6-biphenyl-2-yl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2-
,6(5H)-dicarboxamide I-35
N-hydroxy-6-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-
-carboxamide I-36
N.sup.2-hydroxy-N.sup.6-propyl-7,8-dihydro-1,6-naphthyridine-2,6(5H)--
dicarboxamide I-37
N-hydroxy-7-[(3-phenyl-1H-indol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,7-
-naphthyridine-3- carboxamide I-38
6-benzyl-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide
I-39
N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-5,6,7,8-tetrahydro-1,-
6-naphthyridine-3- carboxamide I-40
N.sup.6-(2-tert-butylphenyl)-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyr-
idine-2,6(5H)-dicarboxamide I-41
7-(4-tert-butylbenzoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridin-
e-3-carboxamide I-42
N-hydroxy-6-[(5-pyridin-2-yl-2-thienyl)carbonyl]-5,6,7,8-tetrahydro-1-
,6-naphthyridine-3- carboxamide I-43
N.sup.2-hydroxy-N.sup.6-(5-methyl-3-phenylisoxazol-4-yl)7,8-dihydro-1-
,6-naphthyridine-2,6(5H)- dicarboxamide I-44
6-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphth-
yridine-3-carboxamide I-45
N.sup.6-(tert-butyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6-
(5H)-dicarboxamide I-46
6-(2,2-dimethylpropanoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyrid-
ine-2-carboxamide I-47
N.sup.6-(2,6-diethylphenyl)-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyri-
dine-2,6(5H)-dicarboxamide I-48
N-hydroxy-7-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-
-carboxamide I-49
6-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphth-
yridine-2-carboxamide I-50
6-(4-tert-butylbenzoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridin-
e-3-carboxamide I-51
N.sup.2-hydroxy-N.sup.6-phenyl-7,8-dihydro-1,6-naphthyridine-2,6(5H)--
dicarboxamide I-52
6-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphth-
yridine-3-carboxamide I-53
6-(biphenyl-4-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyrid-
ine-3-carboxamide I-54
N.sup.2-hydroxy-N.sup.6-(5-phenyl-2-thienyl)-7,8-dihydro-1,6-naphthyr-
idine-2,6(5H)-dicarboxamide I-55
N.sup.2-hydroxy-N.sup.6-(2-phenylethyl)-7,8-dihydro-1,6-naphthyridine-
-2,6(5H)-dicarboxamide I-56
N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-5,6,7,8-tetrahydro-1,6-nap-
hthyridine-3- carboxamide I-57
6-[(4-butoxyphenyl)sulfonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthy-
ridine-3-carboxamide I-58
6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-ca-
rboxamide I-59
N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8-tetrahydro--
1,6-naphthyridine-2- carboxamide I-60
6-[(4-butoxyphenyl)sulfonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthy-
ridine-2-carboxamide I-61
6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-ca-
rboxamide I-62
N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-5,6,7,8-tetrahydro--
1,6-naphthyridine-3- carboxamide I-63
7-cyclopentyl-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbox-
amide I-64
N-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-1,6-naphthy-
ridine-3-carboxamide I-65 3-tert-butylphenyl
3-[(hydroxyamino)carbonyl]-5,8-dihydro-1,7-naphthyridine-7(6H)-
carboxylate I-66
N-hydroxy-7-(methylsulfonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-c-
arboxamide I-67
N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-5,6,7,8-tetrahydropyrido[3-
,4-6]pyrazine-2- carboxamide I-68
6-[(1-acetylpiperidin-4-yl)carbonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-
-naphthyridine-3- carboxamide I-69
N-hydroxy-6-(pyridin-3-ylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridi-
ne-2-carboxamide I-70
N-hydroxy-6-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydro-
-1,6-naphthyridine-2- carboxamide I-71
N-hydroxy-7-(8-oxabicyclo[3.2.1]oct-3-yl)-5,6,7,8-tetrahydro-1,7-naph-
thyridine-3-carboxamide I-72
N-hydroxy-7-(1H-indol-6-ylcarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyrid-
ine-3-carboxamide I-73
6-{[4-(3,5-dimethylisoxazol-4-yl)phenyl]sulfonyl}-N-hydroxy-5,6,7,8-t-
etrahydro-1,6- naphthyridine-2-carboxamide I-74
6-(3,4-dihydro-2H-chromen-4-yl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,-
4-b]pyrazine-2- carboxamide I-75
6-(bicyclo[2.2.1]hept-1-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6--
naphthyridine-2- carboxamide I-76
6-(1-benzothien-2-ylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,4--
b]pyrazine-2- carboxamide I-77 cyclobutyl
2-[(hydroxyamino)carbonyl]-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylat-
e I-78
7-(bicyclo[2.2.1]hept-1-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7--
naphthyridine-3- carboxamide I-79
6-cyclopropyl-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbox-
amide I-80
6-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,4--
b]pyrazine-2- carboxamide I-81
N-hydroxy-6-(2-oxo-2,3-dihydro-1H-indol-4-yl)-5,6,7,8-tetrahydropyrid-
o[3,4-b]pyrazine-2- carboxamide I-82
N.sup.7-biphenyl-4-yl-N.sup.3-hydroxy-5,8-dihydro-1,7-naphthyridine-3-
,7(6H)-dicarboxamide I-83
N-hydroxy-6-(1H-indol-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-b]py-
razine-2-carboxamide I-84
6-(1-adamantylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,4-b]pyra-
zine-2-carboxamide I-85
6-(1-benzothien-3-yl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,4-b]pyrazi-
ne-2-carboxamide I-86
N-hydroxy-6-[(5-methylbicyclo[3.3.1]non-1-yl)carbonyl]-5,6,7,8-tetrah-
ydro-1,6-naphthyridine- 3-carboxamide I-87
7-[(4-benzylpiperidin-4-yl)carbonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,7-
-naphthyridine-3- carboxamide I-88
6-(bicyclo[3.3.1]non-3-ylcarbonyl)-N-hydroxy-5,6,7,8-tetrahydropyrido-
[3,4-b]pyrazine-2- carboxamide I-89
N-hydroxy-6-[(2R)-2-(methylamino)propanoyl]-5,6,7,8-tetrahydro-1,6-na-
phthyridine-2- carboxamide I-90
6-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]-N-hydroxy-5,6,-
7,8-tetrahydro-1,6- naphthyridine-2-carboxamide I-91
7-tert-butyl-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxa-
mide I-92
N-hydroxy-6-[(2R)-3-methyl-2-(methylamino)butanoyl]-5,6,7,8-tetrahydr-
o-1,6-naphthyridine-3- carboxamide I-93
6-[(4-tert-butyl-1,3-thiazol-2-yl)sulfonyl]-N-hydroxy-5,6,7,8-tetrahy-
dropyrido[3,4-b]pyrazine-2- carboxamide I-94
N-hydroxy-6-(pyridin-2-ylcarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridi-
ne-2-carboxamide I-95
6-[2-(4-chlorophenoxy)propanoyl]-N-hydroxy-5,6,7,8-tetrahydropyrido[3-
,4-b]pyrazine-2- carboxamide I-96
7-[(5-cyano-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-5,6,7,8-tetra-
hydro-1,7- naphthyridine-3-carboxamide I-97
N.sup.6-(4-tert-butylphenyl)-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyr-
idine-2,6(5H)-dicarboxamide I-98
N-hydroxy-6-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyri-
dine-2-carboxamide I-99
6-(benzylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-c-
arboxamide I-100
6-[3-(1H-benzimidazol-1-yl)-2-methylpropanoyl]-N-hydroxy-5,6,7,8-tet-
rahydro-1,6- naphthyridine-3-carboxamide I-101
6-(cyclopentylacetyl)-N-hydroxy-5,6,7,8-tetrahydropyrido[3,4-b]pyraz-
ine-2-carboxamide I-102
6-{3-[(dimethylamino)methyl]benzoyl}-N-hydroxy-5,6,7,8-tetrahydro-1,-
6-naphthyridine-2- carboxamide I-103
N.sup.6-[2-(dimethylamino)ethyl]-N.sup.3-hydroxy-7,8-dihydro-1,6-nap-
hthyridine-3,6(5H)-dicarboxamide
I-104
N-hydroxy-6-(1-naphthyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carb-
oxamide I-105
7-(cyclopropylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridi-
ne-3-carboxamide I-106
N.sup.6-cyclohexyl-N.sup.3-hydroxy-7,8-dihydro-1,6-naphthyridine-3,6-
(5H)-dicarboxamide I-107
N-hydroxy-7-(1,2,3,4-tetrahydroisoquinolin-6-yl)-5,6,7,8-tetrahydro--
1,7-naphthyridine-3- carboxamide I-108
N-hydroxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-
-carboxamide I-109
N-hydroxy-6-(2-pyrimidin-2-ylpropanoyl)-5,6,7,8-tetrahydro-1,6-napht-
hyridine-2-carboxamide I-110
N-hydroxy-6-(2-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine--
2-carboxamide I-111
[N-hydroxy-6-(pyridazin-4-ylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthy-
ridine-3-carboxamide I-112
6-{[1-(4-chlorophenyl)cyclobutyl]carbonyl}-N-hydroxy-5,6,7,8-tetrahy-
dro-1,6-naphthyridine-2- carboxamide I-113
7-(3,5-dimethylisoxazol-4-yl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-napht-
hyridine-3-carboxamide I-114
6-{[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]sulfonyl}-N-hydroxy-5,6,7-
,8-tetrahydro-1,6- naphthyridine-3-carboxamide I-115 1-naphthyl
2-[(hydroxyamino)carbonyl]-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxy-
late I-116
6-{[(4-chlorobenzyl)amino]acetyl}-N-hydroxy-5,6,7,8-tetrahydro-1,6-n-
aphthyridine-3- carboxamide I-117
N-hydroxy-6-(piperidin-4-ylcarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyr-
idine-2-carboxamide I-118
N-hydroxy-6-(5-methoxy-1H-indol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthy-
ridine-2-carboxamide I-119
N-hydroxy-6-(2-methylpyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyrid-
ine-2-carboxamide I-120
6-[(2R)-2-(acetylamino)propanoyl]-N-hydroxy-5,6,7,8-tetrahydro-1,6-n-
aphthyridine-3- carboxamide I-121
7-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-5,6,7,8-tetrahydro-1,7-na-
phthyridine-3-carboxamide I-122
6-[(2-chloro-4-cyanophenyl)sulfonyl]-N-hydroxy-5,6,7,8-tetrahydropyr-
ido[3,4-b]pyrazine-2- carboxamide I-123
N-hydroxy-7-[(4-methylpiperidin-4-yl)carbonyl]-5,6,7,8-tetrahydro-1,-
7-naphthyridine-3- carboxamide I-124
N-hydroxy-6-(3-methylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine--
3-carboxamide I-125
N-hydroxy-7-[(2R)-2-phenylpropanoyl]-5,6,7,8-tetrahydro-1,7-naphthyr-
idine-3-carboxamide I-126
N.sup.2-hydroxy-N.sup.6-(5-phenyl-2-thienyl)-7,8-dihydro-1,6-naphthy-
ridine-2,6(5H)-dicarboxamide I-127
6-(4-chlorobenzyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-3--
carboxamide I-128
N-hydroxy-7-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-5,6,7,8-tetrahydro--
1,7-naphthyridme-3- carboxamide I-129 2-chlorophenyl
3-[(hydroxyamino)carbonyl]-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylat-
e I-130
N-hydroxy-7-[phenyl(piperidin-4-yl)acetyl]-5,6,7,8-tetrahydro-1,7-na-
phthyridine-3-carboxamide I-131
N-hydroxy-7-(3-{[(1-isopropyl-4-methylpiperidin-4-yl)carbonyl]amino}-
phenyl)-5,6,7,8- tetrahydro-1,7-naphthyridine-3-carboxamide I-132
N-hydroxy-7-[(methylamino)acetyl]-5,6,7,8-tetrahydro-1,7-naphthyridi-
ne-3-carboxamide I-133
N-hydroxy-6-(piperidin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-b]-
pyrazine-2-carboxamide I-134
N-hydroxy-7-[3-(methylamino)propanoyl]-5,6,7,8-tetrahydro-1,7-naphth-
yridine-3-carboxamide I-135
N-hydroxy-7-[2-(3-piperidin-4-ylphenyl)ethyl]-5,6,7,8-tetrahydro-1,7-
-naphthyridine-3- carboxamide I-136
N-hydroxy-7-(2-piperidin-3-ylethyl)-5,6,7,8-tetrahydro-1,7-naphthyri-
dine-3-carboxamide I-137
7-(2-{[(1,4-dimethylpiperidin-4-yl)carbonyl]amino}pyridin-4-yl)-N-hy-
droxy-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carboxamide I-138
N-hydroxy-7-(pyrrolidin-2-ylcarbonyl)-5,6,7,8-tetrahydro-1,7-naphthy-
ridine-3-carboxamide I-139
7-[(dimethylamino)acetyl]-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyri-
dine-3-carboxamide I-140
N-hydroxy-6-(2-{[(1-isopropyl-4-methylpiperidin-4-yl)carbonyl]amino}-
pyridin-4-yl)-5,6,7,8- tetrahydro-1,6-naphthyridine-2-carboxamide
I-141
7-[(2S)-2-amino-3-methylbutanoyl]-N-hydroxy-5,6,7,8-tetrahydro-1,7-n-
aphthyridine-3- carboxamide I-142
7-(2-amino-3-methylbutanoyl)-N-hydroxy-5,6,7,8-tetrahydro-1,7-naphth-
yridine-3-carboxamide I-143
N-hydroxy-6-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-5,6,7,8-tet-
rahydro-1,6-naphthyridine- 2-carboxamide I-144
7-(2-{[(1-ethyl-4-methylpiperidin-4-yl)carbonyl]amino}pyridin-4-yl)--
N-hydroxy-5,6,7,8- tetrahydro-1,7-naphthyridine-3-carboxamide I-145
7-(4-{[(1-ethyl-4-methylpiperidin-4-yl)carbonyl]amino}phenyl)-N-hydr-
oxy-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carboxamide
4. General Synthetic Methods and Intermediates
[0372] The compounds of the present invention can be prepared by
methods known to one of ordinary skill in the art and/or by
reference to the schemes shown below and the synthetic examples.
Exemplary synthetic routes are set forth in Schemes below and in
the Examples.
##STR00055##
[0373] Scheme 1 shows a general route for the preparation of
compounds of formula vii starting from dimethyl
3-methylpyridine-2,5-dicarboxylate i obtained as described by Wu et
al., Org. Lett. 1999 1(5):745. Treatment of i with sulfuryl
chloride in the presence of a radical initiator such as AIBN
provides access to the chloromethyl containing material ii (Method
A; Menges et al., Intl. App. Pub. No. WO 10/054952). The benzylic
chloride can be displaced with sodium cyanide (Method B) to
generate arylacetonitrile iii which upon treatment with bases such
as sodium hydride or potassium t-butoxide and subsequent reaction
with alkyl halides affords either mono (Method C, Tobisu et al., J.
Am. Chem. Soc. 2009, 131(9):3174) or dialkylated (Method D, Nagata
et al., Tetrahedron: Asymmetry, 2009, 20(21): 2530) compounds of
formula iv. Reduction of the nitrile using Raney Nickel (Method E,
Price et al., Bioorg. Med. Chem. Lett. 2007, 17(2):363) followed by
cyclization with heating in the presence of a base such as sodium
t-butoxide (Method F, Fevig et al., Intl. App. Pub. No. WO
08/064107) generates compounds of formula vi. Removal of the amide
carbonyl in vi is accomplished via reduction in the presence of
suitable hydride delivery agent such as BH.sub.3.THF (Method G) as
described by Di Fabio et al., J. Med. Chem. 2009, 52:3238 leading
to the formation of compound vii.
##STR00056##
[0374] Scheme 2 shows a route for the preparation of compounds of
formula ix. Reaction of the secondary amines represented by
compounds of formula vii with carboxylic acids (R.sup.3--CO.sub.2H)
employing coupling agents such as HBTU or HATU leads to the
formation of the corresponding amide viii (Method H). Conversion of
the methyl ester in viii to a hydroxamate is conducted by reaction
with the potassium salt of hydroxylamine (Method I; Huang et al.,
J. Med. Chem. 2009, 52(21):6757) leading to the formation of
compounds of formula ix.
##STR00057##
[0375] Reaction of the secondary amine in compounds represented by
vii with sulfonyl chlorides (R.sup.3--SO.sub.2Cl; Method J) leads
to the formation of the corresponding sulfonamides x. Conversion of
x to its corresponding hydroxamate is carried out in an analogous
fashion as shown in Scheme 2 (Method I) leading to the formation of
compounds of formula xi. Carbamate derivatives can also be prepared
in a similar fashion by the use of the appropriate chloroformate
(R.sup.3--COOCl).
##STR00058##
[0376] The reaction of compounds of formula vii with isocyanates
(R.sup.3--NCO; Method K) leads to the formation of the
corresponding ureas of formula xii. Conversion of xii to the
corresponding hydroxamates is carried out in an analogous fashions
as shown in Scheme 2 (Method I) leading to the formation of
compounds of formula xiii.
##STR00059##
[0377] The generation of N-alkyl or N-aryl derivatives of
5-substituted-5,6,7,8-tetrahydro-1,7-naphthyridine-3-hydroxamates
as depicted by formula xv is shown in Scheme 5. Treatment of
compounds vii with alkyl halides in the presence of a base such as
potassium carbonate (Method L) or reductive alkylations with
ketones or aldehydes employing reducing agents such as sodium
triacetoxyborohydride (Method M) provides tertiary amines of
formula xiv. Compounds of formula xiv where R.sup.3 is aryl may
also be generated from compounds of formula vii by
palladium-mediated Buchwald type couplings. Conversion of xiv to
the corresponding hydroxamate is carried out in an analogous
fashion to that shown in Scheme 2 (Method I) leading to the
formation of compounds of formula xv.
##STR00060##
[0378] Scheme 6 above depicts a general method for the formation of
7-alkyl derivatives of
5-sustituted-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-hydroxamates
represented by xvii. Initial deprotonation of the lactam vi upon
treatment with sodium hydride at reduced temperatures followed by
alkylation with alkyl halides (Method N; Jin et al., Bioorg. Med.
Chem. Lett. 2009, 19(8):2263) affords compounds of formula xvi.
Conversion of xvi to the corresponding hydroxamate is carried out
in an analogous fashions to that shown in Scheme 2 (Method I)
leading to the formation of compounds of formula xvii.
##STR00061##
[0379] Substitutions at the 6-position of methyl
5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylates may be carried
out as depicted in Scheme 7. The reactive species resulting from
deprotonation of a nitroalkane such as 2-nitropropane can displace
the benzylic halide (Method O) of ii to give compounds represented
by formula xviii. Reduction of the nitro function employing methods
such as catalytic hydrogenation (Method P) to give compounds of
formula xix followed by cyclization in the presence of base (Method
F as described in Scheme 1) forms lactams of formula xx. Reduction
of the lactam gives the corresponding secondary amine of formula
xxi (Method G). It will be appreciated that compounds of the type
xx and xxi can be further functionalized in a similar fashion to
that depicted in Schemes 2-6.
##STR00062##
[0380] Scheme 8 depicts a complimentary route to Schemes 1 and 7
for construction of the substituted tetrahydronaphthyridine system.
Condensation of 1-methyl-3,5-dinitro-2-pyridone xxiii with
carbamate protected piperdones xxii (accessible either via reported
literature methods or via commercial sources) under microwave
irradiation provides the 5-nitropyridine compound of formula xxiv
(Method Q; Henry et al., J. Org. Chem. 2009, 74(5):1932). Reduction
of the nitro group employing any of a variety of methods known to
those skilled in the art gives anilines xxv (Method R). Conversion
of xxv to the bromide employing sodium nitrite or an organic
nitrite derivative such as t-butyl nitrite in the presence of
copper (II) bromide (Sandmeyer reaction) generates compounds of
formula xxvi (Method S; Afonso et al., Biorg. Med. Chem. 1999,
7(9):1845). The newly installed bromide may be carbonylated in the
presence of carbon monoxide gas, methanol and a suitable palladium
catalyst and ligand (Method T; Buchwald et al., J. Org. Chem., 2008
73:7102) to afford the methyl ester xxvii. Boc deprotection is
carried out in the presence of a suitable acid such as HCl (Method
Q) to afford the desired amine of formula xxviii. It will be
appreciated that compounds of the type xxviii can then be further
functionalized in a similar fashion to that depicted in Schemes
2-5.
##STR00063##
[0381] The condensation of compounds of formula xxix, which are
either comerically available or known in the literature, with
pyrrolidine along with azeotropic removal of water employing Dean
Stark conditions provides enamines xxx (Method V; Berlin et al.,
Intl. App. Pub. No. WO 91/07405). Reaction of xxx with excess
propiolamide at elevated temperatures in a suitable solvent such as
toluene, ethanol, xylene or tetrahydrofuran provides access to xxxi
(Method W; Strang et al., EP 1595881). Treatment of the pyridone
xxxi with 1,1,1-trifluoromethanesulfonanilide in the presence of
hindered nitrogen bases in an appropriate solvent with heating
provides triflate xxxii. (Method Y; Carruthers et al., U.S. App.
Pub. No. 2005/0222151). The installation of the methyl ester is
accomplished via carbonylation of compound xxxii in a similar
fashion to that outlined in Scheme 8 (Method T). Cleavage of the
benzyl protecting group to give compounds of formula xxxiv is
achieved by catalytic hydrogenolysis employing standard methodology
as described in "Protective Groups in Organic Synthesis", T. Greene
and P. Wuts, 4.sup.th edition, 2007, John Wiley and Sons (Method
Y). It will be appreciated that compounds of the type xxxiv can be
further functionalized in a similar fashion to that depicted in
Schemes 2-5.
##STR00064##
[0382] Scheme 10 depicts a route for the preparation of compounds
of formula xxxviii. The pyridone xxxv (prepared as described by
Davenport et al., Intl. App. Pub. No. WO 09/121812) can be
converted to the corresponding trfilate xxxvi upon treatment with
1,1,1-trifluoromethanesulfonanilide (Method X; see Scheme 9).
Carbonylation (Method T; see Scheme 9) to generate xxxvii followed
by removal of the Boc protecting group (Method U; see Scheme 8)
affords xxxviii. It will be appreciated that compounds of formula
xxxviii can be further functionalized in a similar fashion to that
depicted in Schemes 2-5. It will also be appreciated that analogous
sequences can be carried out with other suitably substituted
analogs leading to compounds of formula xxxviii with additional
substitution on either ring.
##STR00065##
[0383] Scheme 11 shows a general route for the synthesis of methyl
5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate xlii.
Oxidation of commercially available xxxix with NaIO.sub.4 and
RuO.sub.2 (Method Z; Davenport et al., Intl. App. Pub. No. WO
09/121812) provides lactam xl. Carbonylation (Method T; see Scheme
9) to generate xli followed by removal of the Boc protecting group
(Method U; see Scheme 8) affords xlii. It will be appreciated that
compound xlii can be further functionalized in a similar fashion as
depicted in Scheme 6. It will also be appreciated that analogous
sequences can be carried out with other suitably substituted
analogs leading to compounds of formula xlii with additional
substitution on either ring.
##STR00066##
[0384] Scheme 12 depicts a general route for the preparation methyl
5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate as represented
by xlviii. Treatment of the lactam xliii (prepared as described by
Davenport et al., Intl. App. Pub. No. WO 10/052222) with sodium
hydride in an appropriate solvent followed by the addition of
benzyl bromide provides the corresponding tertiary amide xliv.
Oxidation of xliv with 3-chloroperoxybenzoic acid (m-CPBA) affords
the N-oxide derivative intermediate, which upon subsequent
treatment with phosphorus oxychloride generates the 2-chloro
substituted compound xlv (Method BB; Davenport et al., Intl. App.
Pub. No. WO 10/052222). Carbonylation (Method T; see Scheme 8),
hydrogenation (Method Y; see Scheme 9) and reduction of the lactam
carbonyl (Method G; see Scheme 1) provides compounds of formula
xlviii. It should be appreciated that compounds of the type xlvii
and xlviii can be further functionalized in a similar fashion to
that shown in Schemes 2-6. It will also be appreciated that
analogous sequences can be carried out with other suitably
substituted analogs leading to compounds of formula xlvii and
xlviii with additional substitution on either ring.
##STR00067##
[0385] Scheme 13 shows a general method for the preparation of
ethyl 5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylates of the
general formulas lii and liii. Beginning with ethyl
6-chloro-5-cyanonicotinate xlix (prepared as described by Matasi et
al., Intl. App. Pub. No. WO 06/002051), displacement of the chloro
group with the sodium salt of t-butyl methyl malonate (Method CC;
Morgentin et al., Tetrahedron 2009, 65(4):757-764) to give compound
l followed by reduction of the nitrile with hydrogen in the
presence of catalytic Raney nickel causes cyclization afford
compound li (Method DD; DeMartino et al., U.S. App. Pub. No.
2006/0030582). Decarboxylation of the t-butyl ester of compound li
in the presence of trifluoroacetic acid leads to the formation of
lii (Method EE; DeMartino et al., U.S. App. Pub. No. 2006/0030582).
Removal of the lactam carbonyl is accomplished by similar means to
that depicted in Scheme 1 (Method G) to afford liii. It will be
appreciated that compounds of the type lii and liii can be further
functionalized in a similar fashion to that shown in Schemes 2-6.
It will also be appreciated that analogous sequences can be carried
out with other suitably substituted analogs leading to compounds of
formula lii and liii with additional substitution on the aromatic
ring.
##STR00068##
[0386] Scheme 14 depicts a synthetic route to the preparation of
compounds of formula lvii. Carbonylation of liv (prepared as
described by Gao et al., Intl. App. Pub. No. WO 07/106349) (Method
T; see Scheme 8) affords the methyl ester containing compound lv.
Exhaustive hydrolysis of both the carbamate and ester with KOH in
an appropriate solvent with heat (Method FF; Gao et al., Intl. App.
Pub. No. WO 07/106349) leads to compound lvi. Fischer
esterification of lvi in an alcoholic solvent with catalytic acid
and heat (Method GG) provides compound lvii. It will be appreciated
that compound lvii can then be further functionalized in a similar
fashion to that shown in Schemes 2-5. It will also be appreciated
that analogous sequences can be carried out with other suitably
substituted analogs leading to compounds of formula lvii with
additional substitution on either ring.
##STR00069##
[0387] Scheme 15 depicts a route for the preparation of lx.
Compound lviii (obtained as described by Mitchinson et al., Bioorg.
Med. Chem. Lett. 2004, 14(13):3441-3444) can be hydrolyzed (Method
FF; see Scheme 14) to give amino acid lix. Fischer esterification
(Method GG) affords the amino ester lx. It will be appreciated that
compound lx can then be further functionalized in a similar fashion
to that shown in Schemes 2-5. It will also be appreciated that
analogous sequences can be carried out with other suitably
substituted analogs leading to compounds of formula lx with
additional substitution on either ring.
##STR00070##
[0388] Scheme 16 illustrates a synthetic route for access to
compounds of formula lxiii and lxiv. Treatment of lxi (prepared as
described previously by Kelly et al., Intl. App. Pub. No. WO
06/102610) with diazomethane allows for methylation of the free
hydroxy group to give lxii (Method HH, Ouali et al., Tetrahedron
1980, 36(12):1821). Removal of the benzyl group through
hydrogenation (Method Y; see Scheme 9) affords lxiii.
Alternatively, lxii can be hydrogenated (Method Y; see Scheme 9)
directly to provide lxiv. It will be appreciated that compound
lxiii and lxiv can then be further functionalized in a similar
fashion to that shown in Schemes 2-5. It will also be appreciated
that analogous sequences can be carried out with other suitably
substituted analogs leading to compounds of formulas lxiii and lxiv
with additional substitution on either ring.
5. Uses, Formulation and Administration
[0389] In another aspect, the present invention provides compounds
of formulas (I), (II), (III), (IV), or their sub-formulas for used
in medicine. As discussed above, the present invention provides
compounds and pharmaceutical compositions that are useful as
inhibitors of HDAC enzymes, particularly HDAC6, and thus the
present invention provides compounds for use in treating
proliferative, inflammatory, infectious, neurological or
cardiovascular disorders.
[0390] The compounds and pharmaceutical compositions of the
invention are particularly useful for the treatment of cancer. As
used herein, the term "cancer" refers to a cellular disorder
characterized by uncontrolled or disregulated cell proliferation,
decreased cellular differentiation, inappropriate ability to invade
surrounding tissue, and/or ability to establish new growth at
ectopic sites. The term "cancer" includes, but is not limited to,
solid tumors and bloodborne tumors. The term "cancer" encompasses
diseases of skin, tissues, organs, bone, cartilage, blood, and
vessels. The term "cancer" further encompasses primary and
metastatic cancers.
[0391] In some embodiments, therefore, the invention provides the
compound of formula (I), or a pharmaceutically acceptable salt
thereof; for use in treating cancer. In some embodiments, the
invention provides a pharmaceutical composition (as described
herein) for the treatment of cancer comprising the compound of
formula (I), or a pharmaceutically acceptable salt thereof. In some
embodiments, the invention provides the use of the compound of
formula (I), or a pharmaceutically acceptable salt thereof, for the
preparation of a pharmaceutical composition (as described herein)
for the treatment of cancer. In some embodiments, the invention
provides the use of an effective amount of the compound of formula
(I), or a pharmaceutically acceptable salt thereof, for the
treatment of cancer.
[0392] Non-limiting examples of solid tumors that can be treated
with the disclosed inhibitors include pancreatic cancer; bladder
cancer; colorectal cancer; breast cancer, including metastatic
breast cancer; prostate cancer, including androgen-dependent and
androgen-independent prostate cancer; renal cancer, including,
e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung
cancer, including, e.g., non-small cell lung cancer (NSCLC),
bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung;
ovarian cancer, including, e.g., progressive epithelial or primary
peritoneal cancer; cervical cancer; gastric cancer; esophageal
cancer; head and neck cancer, including, e.g., squamous cell
carcinoma of the head and neck; melanoma; neuroendocrine cancer,
including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma.
[0393] Non-limiting examples of hematologic malignancies that can
be treated with the disclosed inhibitors include acute myeloid
leukemia (AML); chronic myelogenous leukemia (CML), including
accelerated CML and CML blast phase (CML-BP); acute lymphoblastic
leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's
disease (HD); non-Hodgkin's lymphoma (NHL), including follicular
lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell
lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia;
myelodysplastic syndromes (MDS), including refractory anemia (RA),
refractory anemia with ringed siderblasts (RARS), (refractory
anemia with excess blasts (RAEB), and RAEB in transformation
(RAEB-T); and myeloproliferative syndromes.
[0394] In some embodiments, compounds of the invention are suitable
for the treatment of breast cancer, lung cancer, ovarian cancer,
multiple myeloma, acute myeloid leukemia or acute lymphoblastic
leukemia.
[0395] In other embodiments, compounds of the invention are
suitable for the treatment of inflammatory and cardiovascular
disorders including, but not limited to, allergies/anaphylaxis,
acute and chronic inflammation, rheumatoid arthritis; autoimmunity
disorders, thrombosis, hypertension, cardiac hypertrophy, and heart
failure.
[0396] Accordingly, in another aspect of the present invention,
pharmaceutical compositions are provided, wherein these
compositions comprise any of the compounds as described herein, and
optionally comprise a pharmaceutically acceptable carrier, adjuvant
or vehicle. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
[0397] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable prodrugs, salts, esters, salts of such esters, or any
other adduct or derivative which upon administration to a patient
in need is capable of providing, directly or indirectly, a compound
as otherwise described herein, or a metabolite or residue
thereof.
[0398] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of
HDAC6.
[0399] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0400] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0401] In yet another aspect, a method for treating a
proliferative, inflammatory, infectious, neurological or
cardiovascular disorder is provided comprising administering an
effective amount of a compound, or a pharmaceutical composition to
a subject in need thereof. In certain embodiments of the present
invention an "effective amount" of the compound or pharmaceutical
composition is that amount effective for treating a proliferative,
inflammatory, infectious, neurological or cardiovascular disorder,
or is that amount effective for treating cancer. In other
embodiments, an "effective amount" of a compound is an amount which
inhibits binding of HDAC6, and thereby blocks the resulting
signaling cascades that lead to the abnormal activity of growth
factors, receptor tyrosine kinases, protein serine/threonine
kinases, G protein coupled receptors and phospholipid kinases and
phosphatases.
[0402] The compounds and compositions, according to the method of
the present invention, may be administered using any amount and any
route of administration effective for treating the disease. The
exact amount required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the
severity of the infection, the particular agent, its mode of
administration, and the like. The compounds of the invention are
preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disease being treated and the severity of the disease; the activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed, and like factors well known in the
medical arts. The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0403] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0404] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0405] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0406] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0407] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0408] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0409] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0410] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0411] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0412] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0413] In some embodiments, a compound of formula (I) or a
pharmaceutical composition thereof is administered in conjunction
with an anticancer agent. As used herein, the term "anticancer
agent" refers to any agent that is administered to a subject with
cancer for purposes of treating the cancer. Combination therapy
includes administration of the therapeutic agents concurrently or
sequentially. Alternatively, the therapeutic agents can be combined
into one composition which is administered to the patient.
[0414] Non-limiting examples of DNA damaging chemotherapeutic
agents include topoisomerase I inhibitors (e.g., irinotecan,
topotecan, camptothecin and analogs or metabolites thereof, and
doxorubicin); topoisomerase II inhibitors (e.g., etoposide,
teniposide, and daunorubicin); alkylating agents (e.g., melphalan,
chlorambucil, busulfan, thiotepa, ifosfamide, carmustine,
lomustine, semustine, streptozocin, decarbazine, methotrexate,
mitomycin C, and cyclophosphamide); DNA intercalators (e.g.,
cisplatin, oxaliplatin, and carboplatin); DNA intercalators and
free radical generators such as bleomycin; and nucleoside mimetics
(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,
cytarabine, mercaptopurine, thioguanine, pentostatin, and
hydroxyurea).
[0415] Chemotherapeutic agents that disrupt cell replication
include: paclitaxel, docetaxel, and related analogs; vincristine,
vinblastin, and related analogs; thalidomide, lenalidomide, and
related analogs (e.g., CC-5013 and CC-4047); protein tyrosine
kinase inhibitors (e.g., imatinib mesylate and gefitinib);
proteasome inhibitors (e.g., bortezomib); NF-.kappa.B inhibitors,
including inhibitors of I.kappa.B kinase; antibodies which bind to
proteins overexpressed in cancers and thereby downregulate cell
replication (e.g., trastuzumab, rituximab, cetuximab, and
bevacizumab); and other inhibitors of proteins or enzymes known to
be upregulated, over-expressed or activated in cancers, the
inhibition of which downregulates cell replication. In certain
embodiments, a compound of the invention is administered in
conjunction with a proteasome inhibitor.
[0416] Another aspect of the invention relates to inhibiting HDAC6,
activity in a biological sample or a patient, which method
comprises administering to the patient, or contacting said
biological sample with a compound of formula (I), or a composition
comprising said compound. The term "biological sample", as used
herein, generally includes in vivo, in vitro, and ex vivo
materials, and also includes, without limitation, cell cultures or
extracts thereof; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen, tears, or
other body fluids or extracts thereof.
[0417] Still another aspect of this invention is to provide a kit
comprising separate containers in a single package, wherein the
inventive pharmaceutical compounds, compositions and/or salts
thereof are used in combination with pharmaceutically acceptable
carriers to treat disorders, symptoms and diseases where HDAC6
plays a role.
6. Preparation of Exemplary Compounds
Experimental Procedures
Definitions
[0418] AIBN azobisisobutyronitrile [0419] ATP adenosine
triphosphate [0420] DCE dichloroethane [0421] DCM dichloromethane
[0422] DIPEA diisopropylethyl amine [0423] DMAP
4-dimethylaminopyridine [0424] DMF N,N-dimethylformamide [0425]
DMSO dimethylsulfoxide [0426] EDTA ethylenediaminetetraacetic acid
[0427] EtOAc ethyl acetate [0428] EtOH ethanol [0429] FA formic
acid [0430] FBS fetal bovine serum [0431] h hours [0432] HATU
N,N,N',N'-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium
hexafluorophosphate [0433] HEPES
N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) [0434] HRMS
high resolution mass spectrum [0435] IPA isopropyl alcohol [0436]
LC-MS liquid chromatography mass spectrum [0437] m/z mass to charge
[0438] MTBE methyl tert-butyl ether [0439] Me methyl [0440] MEM
minimum essential media [0441] MeOH methanol [0442] min minutes
[0443] MS mass spectrum [0444] MWI microwave irradiation [0445] NMM
N-methyl morpholine [0446] PBS phosphate buffered saline [0447] rt
room temperature [0448] TEA triethylamine [0449] TFA
trifluoroacetic acid [0450] TFAA trifluoroacetic anhydride [0451]
TFFH 1,1,3,3-tetramethylfluoroformamidinium hexafluorophosphate
[0452] THF tetrahydrofuran [0453] TMEDA
N,N,N',N'-tetramethyl-ethane-1,2-diamine [0454] Xantphos
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
[0455] Analytical Methods
[0456] NMR: 1H NMR spectra are run on a 400 MHz Bruker unless
otherwise stated.
[0457] LC-MS: LC-MS spectra are run using an Agilent 1100 LC
interfaced to a micromass Waters.RTM. Micromass.RTM. Zspray.TM.
Mass Detector (ZMD) using the following gradients: [0458] Formic
Acid (FA): Acetonitrile containing zero to 100 percent 0.1% formic
acid in water. [0459] Ammonium Acetate (AA): Acetonitrile
containing zero to 100 percent 10 mM ammonium acetate in water.
[0460] HPLC: Preparative HPLC are conducted using 18.times.150 mm
Sunfire C-18 columns eluting with water-MeCN gradients using a
Gilson instrument operated by 322 pumps with the UV/visible 155
detector triggered fraction collection set to between 200 nm and
400 nm. Mass gated fraction collection is conducted on an Agilent
1100 LC/MSD instrument.
Example 1
methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride
##STR00071##
[0461] Step 1: methyl
6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride
[0462] In a sealed container,
6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid
(1.00 g, 3.73 mmol) was dissolved in MeOH (40.0 mL) and HCl (3.29
mL, 14.9 mmol, 4.0 M in 1,4-dioxane). The resulting solution was
heated at 80.degree. C. for 13 h. The solvent and acid were
completely evaporated to yield methyl
6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride (1.25 g, 100%). LC-MS: (FA) ES+ 283; .sup.1H NMR
(Methanol-d.sub.4, 400 MHz) .delta. 8.08 (d, J=8.0 Hz, 1H), 7.92
(d, J=8.3 Hz, 1H), 7.63 (m, 2H), 7.54 (m, 3H), 4.88 (s, 2H), 4.58
(s, 4H), 3.99 (s, 3H), 3.40 (s, 2H).
Step 2: methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride
[0463] The crude methyl
6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride (1.20 g, 3.76 mmol) was dissolved in MeOH (100 mL)
and thoroughly degassed. Palladium hydroxide (0.185 g, 1.32 mmol)
was added to the solution before being purged with H.sub.2 gas
three times. The reaction was allowed to stir at rt for 13 h under
1 atm of H.sub.2 gas. The mixture was then filtered through a pad
of Celite and rinsed with EtOH. The filtrate was then concentrated
down to yield methyl
5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride
(0.97 g, 100%). LC-MS: (FA) ES+ 220; .sup.1H NMR (Methanol-d.sub.4,
400 MHz) .delta. 8.05 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H),
4.52 (s, 2H), 3.98 (s, 3H), 3.66 (t, J=6.5 Hz, 2H), 3.33 (m,
2H).
Example 2
N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-
e-6-carboxamide Compound I-11
##STR00072##
[0464] Step 1: methyl
2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbo-
xylate
[0465] To a vial containing N-methylpyrrole-2-carboxylic acid
(0.0206 g, 0.165 mmol) was added HATU (0.0627 g, 0.165 mmol) in DMF
(1.00 mL) followed by DIPEA (0.157 mL, 0.9 mmol) in DMF (0.5 mL).
The mixture was shaken at it for 30 min before methyl
5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride
(0.0343 g, 0.15 mmol) in DMF (1.00 mL) was added. The solution was
then shaken at rt for 13 h. The solvent was evaporated and to the
residue was added DCE (3 mL), water (1 mL), and a few drops of
ammonia in MeOH (7 N). After being thoroughly mixed, the layers
were separated and the aqueous layer was extracted with DCE (3 mL).
The combined organic phases were then concentrated to give a solid
residue.
Step 2:
N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroiso-
quinoline-6-carboxamide
[0466] Methyl
2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carbo-
xylate in a vial was dissolved in MeOH (1 mL) and hydroxylamine
potassium salt (0.682 mL, 1.2 mmol; 1.76 M in MeOH) was added. The
solution was shaken at rt for 2 h before acetic acid (0.0682 mL,
1.2 mmol) was added to neutralize the reaction. The solvent was
then completely evaporated and to the residue was added DMSO (1.2
mL). After filtration, the solution was purified by prep-HPLC to
yield
N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoli-
ne-6-carboxamide (0.0073 g, 16.2%). LC-MS: (AA) ES+ 301; .sup.1H
NMR (Methanol-d.sub.4, 400 MHz) .delta. 7.87 (d, J=8.0 Hz, 1H),
7.72 (d, J=8.0 Hz, 1H), 6.86 (t, J=1.8 Hz, 1H), 6.52 (dd, J=3.8,
1.5 Hz, 1H), 6.12 (dd, J=3.8, 2.5 Hz, 1H), 4.96 (s, 2H), 4.07 (t,
J=5.8 Hz, 2H), 3.74 (s, 3H), 3.11 (t, J=6.0 Hz, 2H).
Example 3
[0467] The compounds shown below were prepared in an analogous
fashion to that described in Example 2 starting from the
appropriate starting materials:
TABLE-US-00002 Compound No LC-MS (FA) I-6 ES+ 396 I-49 ES+ 354 I-33
ES+ 333 I-7 ES+ 413 I-22 ES+ 356 I-27 ES+ 319 I-14 ES+ 338 I-2 ES+
236 I-46 ES+ 278 I-19 ES+ 318 I-35 ES+ 328 I-38 ES+ 284
Example 4
N.sup.6-benzyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dicar-
boxamide Compound I-25
##STR00073##
[0468] Step 1: methyl
6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
[0469] To a vial containing benzyl isocyanate (0.0166 g, 0.125
mmol), was added methyl
5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride
(0.0220 g, 0.0962 mmol), DIPEA (0.0586 mL, 0.337 mmol) and DMF (2
mL). The resulting solution was then shaken at rt for 13 h and then
concentrated to give methyl
6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate.
Step 2:
N.sup.6-benzyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5-
H)-dicarboxamide
[0470] To a vial containing methyl
6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76
mmol, 1.76 M in MeOH) and the resulting mixture was shaken at rt
for 13 h. The solution was quenched with acetic acid (0.200 mL,
3.52 mmol) before being concentrated. To the resulting residue was
added DMSO (1.2 mL) and it was purified via prep-HPLC to yield
N.sup.6-benzyl-N.sup.2-hydroxy-7,8-dihydro-1,6-naphthyridine-2,6(5H)-dica-
rboxamide (0.0113 g, 36.0%). LC-MS: (FA) ES+ 327; .sup.1H NMR
(Methanol-d.sub.4, 400 MHz) .delta. 7.86 (d, J=7.8 Hz, 1H), 7.70
(d, J=8.0 Hz, 1H), 7.25-7.19 (m, 5H), 4.68 (s, 2H), 4.39 (s, 2H),
3.79 (t, J=6.0 Hz, 2H), 3.03 (t, J=6.0 Hz, 2H).
Example 5
[0471] The compounds shown below were prepared in an analogous
fashion to that described in Example 4 starting from the
appropriate starting materials:
TABLE-US-00003 Compound No LC-MS (FA) I-45 ES+ 293 I-43 ES+ 394
I-40 ES+ 369 I-51 ES+ 313 I-17 ES+ 319 I-13 ES+ 371 I-34 ES+ 389
I-8 ES+ 327 I-54 ES+ 395 I-55 ES+ 341 I-36 ES+ 279 I-47 ES+ 369
I-16 ES+ 293
Example 6
6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxa-
mide Compound I-61
##STR00074##
[0472] Step 1: methyl
6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
[0473] To a microwave vial containing n-butanesulfonyl chloride
(0.0352 g, 0.225 mmol), was added methyl
5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride
(0.0288 g, 0.15 mmol), TEA (0.167 mL, 1.2 mmol), DMAP (1.83 mg,
0.015 mmol), and DMF (2 mL). The mixture was shaken at rt for 13 h.
The solvent was then completely evaporated to yield a solid. LC-MS:
(FA) ES+ 313.
Step 2:
6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-
-carboxamide
[0474] To a microwave vial containing methyl
6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76
mmol, 1.76 M in MeOH). The solution was shaken at rt for 1 h, then
acetic acid (0.102 mL, 1.8 mmol) was added to quench excess base.
The solvent was then concentrated. To the resulting residue was
added DMSO (1.2 mL) and after filtration, the solution underwent
purification via prep-HPLC to give
6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-c-
arboxamide (13.3 mg, 28.3%). LC-MS: (FA) ES+ 314; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta. 7.97 (d, J=8.1 Hz, 1H), 7.76
(d, J=7.9 Hz, 1H), 4.59 (s, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.13 (m,
4H), 1.77 (m, 2H), 1.47 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).
Example 7
[0475] The compounds shown below were prepared in an analogous
fashion to that described in Example 6 starting from the
appropriate starting materials:
TABLE-US-00004 Compound No LC-MS (FA) I-60 ES+ 406 I-59 ES+ 402
Example 8
methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate
hydrochloride
##STR00075##
[0476] Step 1: t-butyl
3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate
[0477] To a flask containing
3-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine (1.50 g, 7.04 mmol),
was added THF (70 mL, 863 mmol), di-tert-butyldicarbonate (1.77 g,
8.10 mmol), TEA (5.89 mL, 42.2 mmol), and DMAP (43.0 mg, 0.352
mmol). The solution was stirred at rt for 4 h. The solvent was then
concentrated. To the resulting residue was added EtOAc (150 mL) and
water (50 mL). After separation, the aqueous layer was extracted
with EtOAc (2.times.150 mL). The combined organic layers were then
washed with water (2.times.100 mL), brine (100 mL), dried
(Mg.sub.2SO.sub.4), and concentrated to yield tert-butyl
3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.15 g,
97.5%). LC-MS: (FA) ES+ 314; .sup.1H NMR (Methanol-d.sub.4, 300
MHz) .delta. 8.43 (s, 1H, 7.83 (s, 1H), 4.60 (s, 2H), 3.73 (t,
J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 1.48 (s, 9H).
Step 2: 6-t-butyl 3-methyl
7,8-dihydro-1,6-naphthyridine-3,6(5H)-dicarboxylate
[0478] A solution of tert-butyl
3-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.15 g,
6.86 mmol), TEA (9.57 mL, 68.7 mmol), MeOH (25 mL) and DMSO (12.4
mL) was thoroughly degassed with N.sub.2 gas for 15 min. Then
1,3-bis(diphenylphosphino)propane (0.442 g, 1.07 mmol) and
palladium(II)acetate (0.240 g, 1.07 mmol) were quickly added to the
solution. After purging the solution twice with CO gas, the
solution was left to stir at 80.degree. C. for 6 h under 1 atm of
CO. MeOH was concentrated before EtOAc (400 mL) and water (100 mL)
were added to the remaining DMSO residue. After separation, the
aqueous phases were extracted with EtOAc (2.times.300 mL). Then
combined organic phases were then washed with brine (100 mL), 1 N
HCl (100 mL), dried (MgSO.sub.4), and concentrated. Purification
via flash column chromatography (EtOAc: hexanes, 1:4 to 1:1)
afforded a yellow solid (1.79 g, 89.2%). LC-MS: (FA) ES+ 293;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.02 (s, 1H), 8.03 (s,
1H), 4.64 (s, 2H), 3.95 (s, 3H), 3.77 (t, J=6.0 Hz, 2H), 3.07 (t,
J=6.0 Hz, 2H), 1.50 (s, 9H).
Step 3: methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate
hydrochloride
[0479] To a flask was added 6-tert-butyl 3-methyl
7,8-dihydro-1,6-naphthyridine-3,6(5H)-dicarboxylate (1.79 g, 6.12
mmol) and hydrochloric acid (23.0 mL, 91.8 mmol, 4.0 M in
1,4-dioxane). The mixture was stirred at rt for 1 h. The solvent
was completely evaporated to yield methyl
5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate hydrochloride
(1.64 g, 100%). LC-MS: (FA) ES+ 193.
Example 9
Synthesis of
N-hydroxy-6-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-car-
boxamide Compound I-32
##STR00076##
[0481] The title compound was prepared in an analogous fashion to
that described in Example 2 starting from the appropriate starting
materials. Yield: 36.9%. LC-MS (FA): ES+ 328; .sup.1H NMR
(Methanol-d.sub.4, 400 MHz) .delta. 8.72 (s, 1H), 7.96 (br, 1H),
7.47 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.92
(m, 2H), 3.84 (s, 3H), 3.10 (t, J=5.8 Hz, 2H).
Example 10
[0482] The compounds below were prepared in an analogous fashion to
that described in Example 2 starting from appropriate starting
materials:
TABLE-US-00005 Compound No LC-MS (FA) I-20 ES+ 284 I-29 ES+ 413
I-50 ES+ 353 I-42 ES+ 381 I-39 ES+ 301 I-44 ES+ 338 I-53 ES+ 374
I-5 ES+ 389 I-56 ES+ 318 I-52 ES+ 354 I-31 ES+ 356 I-12 ES+ 333 I-1
ES+ 319 I-23 ES+ 396 I-30 ES+ 278
Example 11
N-hydroxy-6-(4-(trifluoromethyl)phenylsulfonyl)-5,6,7,8-tetrahydro-1,6-nap-
hthyridine-3-carboxamide Compound I-62
##STR00077##
[0484] The title compound was prepared in an analogous fashion to
that described in Example 6 starting from the appropriate starting
materials. Yield: 66.2%. LC-MS (FA): ES+ 402; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta. 8.66 (s, 1H), 8.08 (d, J=8.1
Hz, 2H), 7.92 (m, 3H), 4.43 (s, 2H), 3.58 (t, J=6.0 Hz, 2H), 3.05
(t, J=6.0 Hz, 2H).
Example 12
[0485] The compounds below were prepared in an analogous fashion to
that described in Example 6 starting from the appropriate starting
materials:
TABLE-US-00006 Compound No LC-MS (FA) I-57 ES+ 406 I-58 ES+ 314
Example 13
methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride
##STR00078##
[0486] Step 1: methyl
6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate
hydrochloride
[0487] A round-bottom flask containing 7-tert-butyl 3-methyl
5,6-dihydro-1,7-naphthyridine-3,7-(8H)-dicarboxylate (0.470 g, 1.61
mmol) and hydrochloric acid (6.03 mL, 24.1 mmol, 4.0 M in
1,4-dioxane) was stirred at rt for 1 h. The solution was then
completely evaporated to yield methyl
5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride
(0.440 g, 100%). LC-MS: (FA) ES+ 193; .sup.1H NMR
(Methanol-d.sub.4, 400 MHz) .delta. 9.26 (s, 1H), 8.87 (s, 1H),
4.83 (s, 2H), 4.03 (s, 3H), 3.69 (m, 2H), 3.43 (t, J=5.5 Hz,
2H).
Example 14
N-hydroxy-7-(4-methoxybenzoyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carb-
oxamide Compound I-48
##STR00079##
[0489] The title compound was prepared in an analogous fashion to
that described in Example 2 starting from the appropriate starting
materials. Yield: 29.3%. LC-MS (FA): ES+ 328; .sup.1H NMR
(Methanol-d.sub.4, 400 MHz) .delta. 8.70 (s, 1H), 7.99 (s, 1H),
7.47 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.86
(m, 2H), 3.84 (s, 3H), 3.02 (t, J=5.6 Hz, 2H).
Example 15
[0490] The compounds below were prepared in an analogous fashion to
that described in Example 2 starting from appropriate starting
materials:
TABLE-US-00007 Compound No LC-MS (FA) I-28 ES+ 333 I-21 ES+ 236
I-10 ES+ 319 I-15 ES+ 356 I-41 ES+ 354 I-37 ES+ 413 I-4 ES+ 354 I-9
ES+ 318 I-18 ES+ 338 I-24 ES+ 301 I-3 ES+ 294
Example 16
HDAC6 Enzyme Assay
[0491] To measure the inhibition of HDAC6 activity, purified human
HDAC6 (BPS Bioscience; Cat. No. 5006) is incubated with substrate
Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No.
I-1925) for 1 hour at 30.degree. C. in the presence of test
compounds or vehicle DMSO control. The reaction is stopped with the
HDAC inhibitor trichostatin A (Sigma; Cat. No. T8552) and the
amount of Arg-Gly-Lys-AMC generated is quantitated by digestion
with trypsin (Sigma; Cat. No. T1426) and subsequent measurement of
the amount of AMC released using a fluorescent plate reader
(Pherastar; BMG Technologies) set at Ex 340 nm and Em 460 nm.
Concentration response curves are generated by calculating the
fluorescence increase in test compound-treated samples relative to
DMSO-treated controls, and percentage inhibition values at a single
concentration or enzyme inhibition (IC.sub.50) values are
determined from those curves. One skilled in the art will
appreciate that the values generated either as percentage
inhibition at a single concentration or IC.sub.50 values are
subject to experimental variation.
Example 17
Nuclear Extract HDAC Assay
[0492] As a screen against Class I HDAC enzymes, HeLa nuclear
extract (BIOMOL; Cat. No. KI-140) is incubated with
Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No.
I-1925) in the presence of test compounds or vehicle DMSO control.
The HeLa nuclear extract is enriched for Class I enzymes HDAC1, -2
and -3. The reaction is stopped with the HDAC inhibitor
Trichostatin A (Sigma; Cat. No. T8552) and the amount of
Arg-Gly-Lys-AMC generated is quantitated by digestion with trypsin
(Sigma; Cat. No. T1426) and subsequent measurement of the amount of
AMC released using a fluorescent plate reader (Pherastar; BMG
Technologies) set at Ex 340 nm and Em 460 nm. Concentration
response curves are generated by calculating the fluorescence
increase in test compound-treated samples relative to DMSO-treated
controls, and enzyme inhibition (IC.sub.50) values are determined
from those curves.
Example 18
Western Blot and Immunofluorescence Assays
[0493] Cellular potency and selectivity of compounds are determined
using a published assay (Haggarty et al., Proc. Natl. Acad. Sci.
USA 2003, 100 (8): 4389-4394) using Hela cells (ATCC cat#
CCL-2.TM.) which are maintained in MEM medium (Invitrogen)
supplemented with 10% FBS; or multiple myeloma cells RPMI-8226
(ATCC cat# CCL-155.TM.) which are maintained in RPMI 1640 medium
(Invitrogen) supplemented with 10% FBS. Briefly, cells are treated
with inhibitors for 6 or 24 h and either lysed for Western
blotting, or fixed for immunofluorescence analyses. HDAC6 potency
is determined by measuring K40 hyperacetylation of alpha-tubulin
with an acetylation selective monoclonal antibody (Sigma cat#
T7451) in IC50 experiments. Selectivity against Class I HDAC
activity is determined similarly using an antibody that recognizes
hyperacetylation of histone H4 (Upstate cat#06-866) in the Western
blotting assay or nuclear acetylation (Abeam can ab21623) in the
immunofluorescence assay.
Example 19
In Vivo Tumor Efficacy Model
[0494] Female NCr-Nude mice (age 6-8 weeks, Charles River Labs) are
aseptically injected into the subcutaneous space in the right
dorsal flank with 1.0-5.0.times.10.sup.6 cells (SKOV-3, HCT-116,
BxPC3) in 100 .mu.L of a 1:1 ratio of serum-free culture media
(Sigma Aldrich) and BD Matrigel.TM. (BD Biosciences) using a 1 mL
263/8 gauge needle (Becton Dickinson Ref#309625). Alternatively,
some xenograft models require the use of more immunocompromised
strains of mice such as CB-17 SCID (Charles River Labs) or NOD-SCID
(Jackson Laboratory). Furthermore, some xenograft models require
serial passaging of tumor fragments in which small fragments of
tumor tissue (approximately 1 mm.sup.3) are implanted
subcutaneously in the right dorsal flank of anesthetized (3-5%
isoflourane/oxygen mixture) NCr-Nude, CB-17 SCID or NOD-SCID mice
(age 5-8 weeks, Charles River Labs or Jackson Laboratory) via a
13-ga trocar needle (Popper & Sons 7927). Tumor volume is
monitored twice weekly with Vernier calipers. The mean tumor volume
is calculated using the formula V=W.sup.2.times.L/2. When the mean
tumor volume is approximately 200 mm.sup.3, the animals are
randomized into treatment groups of ten animals each. Drug
treatment typically includes the test compound as a single agent,
and may include combinations of the test compound and other
anticancer agents. Dosing and schedules are determined for each
experiment based on previous results obtained from
pharmacokinetic/pharmacodynamic and maximum tolerated dose studies.
The control group will receive vehicle without any drug. Typically,
test compound (100-200 .mu.L) is administered via intravenous
(27-ga needle), oral (20-ga gavage needle) or subcutaneous (27-ga
needle) routes at various doses and schedules. Tumor size and body
weight are measured twice a week and the study is terminated when
the control tumors reach approximately 2000 mm.sup.3, and/or if
tumor volume exceeds 10% of the animal body weight or if the body
weight loss exceeds 20%.
[0495] The differences in tumor growth trends over time between
pairs of treatment groups are assessed using linear mixed effects
regression models. These models account for the fact that each
animal is measured at multiple time points. A separate model is fit
for each comparison, and the areas under the curve (AUC) for each
treatment group are calculated using the predicted values from the
model. The percent decrease in AUC (dAUC) relative to the reference
group is then calculated. A statistically significant P value
suggests that the trends over time for the two treatment groups are
different.
[0496] The tumor measurements observed on a date pre-specified by
the researcher (typically the last day of treatment) are analyzed
to assess tumor growth inhibition. For this analysis, a T/C ratio
is calculated for each animal by dividing the tumor measurement for
the given animal by the mean tumor measurement across all control
animals. The T/C ratios across a treatment group are compared to
the T/C ratios of the control group using a two-tailed Welch's
t-test. To adjust for multiplicity, a False Discovery Rate (FDR) is
calculated for each comparison using the approach described by
Benjamini and Hochberg, J. R. Stat. Soc. B 1995, 57:289-300.
[0497] As detailed above, compounds of the invention inhibit HDAC6.
In certain embodiments, compounds of the invention inhibit HDAC6
with the percent inhibition at a concentration of 1.235 .mu.M shown
in the table below.
TABLE-US-00008 Percent Percent Inhibition at Inhibition at Compound
1.235 .mu.M Compound 1.235 .mu.M I-3 95.255 I-9 95.195 I-38 60.24
I-4 97.23 I-30 84.99 I-37 93.685 I-23 91.95 I-48 91.115 I-1 87.79
I-41 93.365 I-12 94.49 I-15 95.59 I-31 93.775 I-10 84.57 I-52 97.36
I-21 73.89 I-56 92.985 I-28 91.895 I-5 93.44 I-16 27.33 I-32 93
I-47 34.335 I-53 96.92 I-36 26.515 I-44 94.87 I-55 58.26 I-39 92.45
I-54 67.155 I-42 97.53 I-8 40.43 I-50 95.12 I-34 48.16 I-29 97.82
I-13 70.64 I-35 66.98 I-17 41.19 I-19 79.49 I-51 63.365 I-46 58.99
I-25 60.415 I-2 34.13 I-40 50.395 I-14 89.92 I-43 23.37 I-27 51.24
I-45 38.985 I-22 90.205 I-20 58.6 I-7 79.04 I-59 67.43 I-11 73.9
I-58 94.465 I-33 68.79 I-61 -3.95 I-49 94.1 I-57 94.12 I-6 81.38
I-60 75.78 I-24 92.33 I-62 94.65 I-18 97.215 I-26 93.995
[0498] As detailed above, compounds of the invention are selective
for HDAC6 over other Class I HDAC enzymes. In some embodiments, the
ratio of HDAC IC50 (as obtained in the nuclear extract assay
described above) to HDAC6 IC50 is less than 5 (HDAC IC50/HDAC6
IC50). In certain embodiments, the ratio of HDAC IC50 to HDAC6 IC50
is between 5 and 10. In certain embodiments, the ratio of HDAC IC50
to HDAC6 IC50 is between 10 and 100.
[0499] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments, which utilize the compounds and methods
of this invention. Therefore, it will be appreciated that the scope
of this invention is to be defined by the appended claims rather
than by the specific embodiments, which have been represented by
way of examples.
* * * * *